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Porcine Epidemic Diarrhea Virus: An Updated Overview of Virus Epidemiology, Virulence Variation Patterns and Virus–Host Interactions

Yuanzhu Zhang, Yiwu Chen, Jian Zhou and 7 more

Viruses · 2022 · Review · CC BY

doi:10.3390/v14112434

Abstract

The porcine epidemic diarrhea virus (PEDV) is a member of the coronavirus family, causing deadly watery diarrhea in newborn piglets. The global pandemic of PEDV, with significant morbidity and mortality, poses a huge threat to the swine industry. The currently developed vaccines and drugs are only effective against the classic GI strains that were prevalent before 2010, while there is no effective control against the GII variant strains that are currently a global pandemic. In this review, we summarize the latest progress in the biology of PEDV, including its transmission and origin, structure and function, evolution, and virus–host interaction, in an attempt to find the potential virulence factors influencing PEDV pathogenesis. We conclude with the mechanism by which PEDV components antagonize the immune responses of the virus, and the role of host factors in virus infection. Essentially, this review serves as a valuable reference for the development of attenuated virus vaccines and the potential of host factors as antiviral targets for the prevention and control of PEDV infection.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Epidemiology of PEDV

Porcine epidemic diarrhea (PED) is an infectious intestinal disease caused by the porcine epidemic diarrhea virus (PEDV). PEDV mainly affects piglets more severely than adult pigs, generally showing symptoms such as vomiting, liquid diarrhea, dehydration, anorexia, and weight loss. The presence of PEDV was first reported on a farm in the United Kingdom in 1971 and the virus was first isolated in Belgium in 1978. In 1984, China confirmed the existence of PED antigen for the first time through the serum antigen test. In early 2004, PEDV with low mortality did not receive much global attention. By 2010, high-mortality strains of PEDV emerged and spread globally, having an increasing impact on the global swine industry. In this regard, a comprehensive understanding of PEDV has become increasingly urgent. Here, we conduct a comprehensive review of the epidemiology of PEDV, including discussing the worldwide spread of PEDV variants, exploring the origins of PEDV variants around the world, and describing the structure and function of PEDV.

1.1. The Morbidity and Mortality of PEDV

Mortality was often associated with the age of recipient animals after PEDV infection. In aged animals, although the morbidity may be close to 100%, the mortality rate is very low, between 1% and 3%. However, the morbidity in piglets is more severe, with an average of 50% mortality in piglets within two weeks of birth. In 2004, PEDV infection caused a regional outbreak with a low fatality rate. At this point, the morbidity in piglets was 46.4%, and the mortality rate was only 6.16%. In the winter of 2010, a new variant of highly pathogenic GII PEDV appeared in southern China, which increased the morbidity and mortality of PEDV to more than 80–100%. More than a million piglets, even vaccinated ones, died on pig farms in southern China, dealing a devastating blow to the swine industry. In 2013, according to statistics, morbidity in the United States was nearly 100%, and piglet mortality was 90–95%. As of 2014, the mortality rate of piglets infected with pathogenic strains in Germany was more than 70%. From 2016 to 2018, the mortality rate of Mexican piglets was 80–95%. In recent years, the most popular GII PEDV highly pathogenic variant has gradually spread around the world, and the threat to the global swine industry has become more and more serious.

1.2. Transmission of PEDV

Transmission by direct and indirect contact is the main route of PEDV transmission between pigs. PEDV is transmitted between pigs at different ages and usually first infects finishing pigs, then the virus spreads to pregnant sows in the farrowing house, and subclinically infected sows then transmit PEDV to suckling piglets, eventually causing an epidemic of high mortality in piglets. Here, we summarize several routes of PEDV transmission between pigs (Figure 1).

PEDV spreads in several different ways during infection, and one of the most common is the fecal–oral route, that is, direct or indirect transmission through porcine feces, vomit, and other contaminants produced by the livestock process. PEDV can be infected through the route of transmission from porcine feces to the nasal cavity, known as the fecal–nasal route. In addition, PEDV can also be transmitted vertically to piglets through sow milk. According to a study by Gallien et al. (2018), the presence of PEDV can be detected in the semen of PEDV-infected boars, and prolonged virus shedding can be observed in the sperm-rich fraction, proving that PEDV can be sexually transmitted through boar semen. A recent study showed that PEDV infected by nasal epithelium can be transferred to CD3+ T lymphocytes through synapses, and finally reaches the intestinal mucosa through blood circulation, resulting in intestinal infection, which is the mechanism of PEDV infection from the nasal cavity to the intestinal epithelium, and is also important evidence for aerosol transmission. In addition to pig–to–pig infection, the transmission of PEDV can also occur through contact with contaminated equipment, contaminated vehicles used for animal transport, or farm employees.

1.3. Genotyping, Distribution, and Origin of PEDV

PEDV continuously evolves in the process of adapting to environmental changes, and its frequent variants lead to the emergence of various virulent strains. At present, researchers have classified PEDV into the GI classical genogroup and the GII variant genogroup. Genogroups GI and GII further evolved separately, and finally formed five subgroups (GIa, GIb, GIIa, GIIb, and GIIc). To further clarify the genotype characteristics of PEDV and the global prevalence of each genogroup, we discuss the distribution and origin of each genogroup of PEDV in Table 1.

Genogroup GI is divided into two subgroups, GIa and GIb. The GIa subgroup mainly consists of classic CV777, DR13, SM98, and other early strains, distributed in Europe and Asia. The GIb strains mainly originate from Asian countries, especially China, which are generally early strains or cell-adapted attenuated vaccine strains caused by the insertion or deletion of the PEDV S gene. Compared with the GIa with a certain virulence, the GIb strains are less virulent, and many attenuated strains have been identified as candidates for attenuated vaccines, which we propose to term “S-Indel vaccine strains”. The most typical strains in the GIb subgroup include the early strain JS-2004-2 and vaccine strains, such as the attenuated CV777, attenuated DR13, and SD-M. In addition to the typical attenuated vaccine strains, there is also the CV777 vaccine strain-like AH-M classic strain, which has been circulating in China recently.

Since 2010, genogroup GII strains have been predominant globally, especially in China. The GI and GII strains are not genetically closely related, and one of the most typical differences is that the GII strains have 11 different amino acid mutations (I116T, I356T, E365Q, T549S, G594S, N724S, A959V, S1044A, G1173D, S1232R, and R1298Q). Subgroup GIIa is an emerging non-S INDEL strain recombined within the S protein domain with higher virulence than genogroup GI, including those prevalent in Asia (AH2012, LZW, ZMDZY, GDZQ, and Tottori2), and those prevalent in North America (Colorado, PC21A, and PC177), which occurs more frequently in Asia. The GIIb subgroup is also a highly virulent non-S INDEL strain recombined within the S protein domain. All GIIb strains are currently circulating in China, including AJ1102, LC, AH2012-12, YN1, and other typical strains. However, no potential recombination occurred in the SH strain of GIIb, suggesting that amino acid substitutions in the S protein are also a pattern for the GIIb subgroup. The third important subtype of GII is GIIc, a kind of S-INDEL strain produced by recombination of the subgroups GIa and GIIa and the structural changes of the S gene. These strains commonly have one amino acid insertion (aa 161–162) and two amino acid deletions (aa 59–62 and aa 140) in the N-terminal region of the S protein. Compared with other subgroups, GIIc also has three unique amino acid substitutions (L76, A/S92 and H/T113) and antigenic drift due to amino acid substitutions. The less virulent GIIc strains, such as OH851, 15V010, CH/HNQX-3/14, and ZL29, are mainly disseminated and prevalent in Europe, with a minority from the United States and Asia.

PEDV is mainly prevalent in Asia, North America, and Europe. Exploring the global prevalence and transmission of PEDV is thus relevant to understanding the origin of PEDV in various continents. The sporadic outbreaks of PEDV in 2005 occurred only in Asia, and they all belonged to the classic GIa strains. In October 2010, a highly virulent GII variant which was different from the classic strain CV777 appeared in China for the first time. Since then, China, South Korea, Japan, Vietnam, Thailand, and the Philippines have suffered an outbreak of PEDV, successively. Among them, two pandemic strains, MG868 and BIG1024, emerged in South Korea, and these are likely to be the origin of the subsequent outbreak of PEDV in Asia. In April 2013, when a highly virulent non-S INDEL GII strain was detected for the first time in the United States, PEDV appeared in the United States and rapidly spread throughout North America, including Canada and Mexico. Here, the three representative emerging strains, MN, IA1, and IA2, were closely related to the AH2012 strain in China; however, the potential parental PEDV strain from which the North American outbreak originated has not been identified. In 2014, a newly discovered mild PEDV S-INDEL strain (GIIc) emerged in Germany and began to circulate in many European countries such as the Netherlands, France, Belgium, Portugal and Austria. These mild variants were speculated to be homologous with the PEDV variant strain OH851, which was first detected in the United States earlier that same year.

1.4. Virion Structure and Function of PEDV

PEDV is a single-stranded positive-sense RNA virus with a diameter of 95–190 nm, a typical nested crown, and a genome size of approximately 28 kb, belonging to the genus alphacoronavirus. PEDV consists of seven open reading frames (ORF1a, ORF1b, and ORF2–6), of which ORF1a (nt 297–12650) and ORF1b (nt 12605–20641) encode a total of sixteen nonstructural proteins, including nsp1~nsp16; ORF2 and ORF4–6 encode four structural proteins, including the spike (S) protein of 150–220 kDa, the envelope (E) protein of 7 kDa, the membrane (M) protein of 20–30 kDa, and the nucleocapsid (N) protein of 58 kDa; ORF3 encodes an accessory protein ORF3 (Figure 2).

According to the molecular structure of the PEDV genome drawn, the ORF1a and ORF1b regions start from the 5′-end cap, and the polyproteins ppla and pp1ab translated from its replicase gene are post-translationally cleaved by internal proteases, resulting in 16 mature end-product nonstructural proteins nsp1–16, mainly playing a role in virus infection; this can inhibit the immune responses of the host and create a favorable environment for virus infection and proliferation.

The S protein is located on the outer layer of the viral envelope, a type I glycoprotein, which is the most basic functional protein in PEDV. Compared with the homology analysis of the corresponding regions of other coronaviruses, the S protein of PEDV is divided into two parts: S1 (19–726 aa) and S2 (727–1383 aa). The S1 subunit contains two RBDs, S1-NTD and S1-CTD, which mainly bind to receptors to facilitate viral attachment. The S2 subunit contains three domains, two heptapeptide repeat domains (HR1 and HR2, 978–1117 aa and 1274–1313 aa) and a transmembrane domain (TM, 1324–1346 aa), which mainly promote viral membrane fusion. Four B cell epitopes have been characterized in the S protein, including the core neutralizing epitope (COE) (499–638 aa) on the S1 subunit, the epitopes SS2 (748–755 aa), SS6 (764–771 aa) and 2C10 (1368–1374 aa) on the S2 subunit, which become the main target for the development of vaccines or antibodies. The S protein plays an important role in viral pathogenicity, tissue tropism, infection, dissemination, and the trypsin-dependent proliferation of PEDV.

The accessory protein ORF3 is the characteristic protein of coronavirus and the only accessory protein in PEDV. ORF3 has a homotetrameric structure comprising four transmembrane regions, which are generally encoded by sequences located between the viral S and E genes. The ORF3 protein of PEDV has a similar function to that of SARS coronavirus, and the intact ORF3 protein can function as an ion channel and regulate virus release during infection. In addition, the ORF3 gene of PEDV has been shown to prolong the S phase of host cells by promoting the formation of vesicular structures, indicating its importance in the process of PEDV replication. In general, ORF3 plays an important adjunctive role in PEDV infection, especially in the interaction between the virus and host cells.

The E protein is mainly localized in the endoplasmic reticulum, with a minor amount in the nucleus, whose molecular structure is divided into three regions, including a short amino-terminal hydrophilic region, an alpha-helical transmembrane domain of approximately 25 aa in length, and a long carboxyl-terminal region. E protein functionally does not affect host cell proliferation and cell cycle, but it is implicated in the inflammatory response and persistence of PEDV infection. Besides this, the E protein can also help evade host innate immunity by inhibiting RIG-I-mediated signaling. Finally, the E protein tends to induce membrane curvature, and plays an important role in virion morphogenesis, assisting in the assembly of coronaviruses.

The M protein is an important membrane glycoprotein within the envelope, and the most abundant component in the viral envelope, which can interact with the E and S proteins encoded upstream of the viral structure, to complete the envelope assembly of the coronavirus. The M protein can also interact with ORF3, and together with the N protein, participate in the assembly and budding of virus particles. Additionally, the M protein suppresses the host immune responses by inducing neutralizing antibodies or inhibiting interferon-β (IFN-β) activity, while inducing cell-cycle arrest at S-phase through the cyclin A pathway during viral infection.

The N protein, called the nucleocapsid protein, is the main structural protein involved in the formation of the helical nucleocapsid, together with the viral genomic RNA. It is currently known that in coronaviruses, the N protein is the only phosphorylated basic structural protein that is required for the efficient replication and transcription of viral RNA, and assists in the process of organizing the viral genome to help virion assembly. During viral infection, PEDV N can regulate the cell cycle and suppress the immune responses by IFN regulatory factor 3 (IRF3). Meanwhile, PEDV N induces endoplasmic reticulum stress and inhibits cell-induced apoptosis through interaction with cellular phosphoproteins. Surprisingly, the PEDV N protein may help to enhance the replication of viruses closely related to PEDV, such as porcine reproductive and respiratory syndrome virus (PRRSV), whereas it is inactive against unrelated viruses.

2. Factors Affecting Pathogenicity

Compared to GIIc strains with lower mortality rates in Europe, the prevalence of highly virulent GII strains with almost 100% mortality in Asia and the Americas caused greater losses to the swine industry. Moreover, due to the high heterogeneity of PEDV, vaccines developed for GI strains cannot effectively prevent and treat infections caused by highly virulent GII strains. Comparing the heterogeneity between variant strains and classical strains and analyzing the impact of these variants on virulence changes will help to parse out important factors affecting virus virulence and assess in a timely way the potential threat of emerging variants to the swine industry. Here, we describe the effects of PEDV viral proteins on virulence change and growth adaptation of strains from the perspective of gene heterogeneity. Finally, we try to find the key amino acids on the S protein that affect virus virulence and cell growth fitness, which have important reference values for the development of attenuated vaccines.

2.1. Variation in Structural/Accessory/Non-Structural Proteins

The viral S protein, which is involved in receptor recognition and facilitates membrane fusion and anchoring, is a major factor in host tropism and pathogenesis of coronaviruses and may play important roles in virulence and host or tissue tropism. To explore the effect of strain variation on virus virulence, in Table 2, we summarize the amino acid indels in the genome of several variant strains with the highly virulent parental strains as a reference.

The S1 subunit of the S protein is an important determinant of PEDV virulence, using reverse genetics. Of these attenuated PEDV strains, most have a deletion in a stretch of amino acid sequences of the S gene, which clarifies the role of the S protein in virulence. The PEDV S protein contains two sorting motifs in the cytoplasmic tail: endocytosis signal-YxxΦ and ER retrieval signal (ERRS)-KVHVQ. Some studies have reported that deletion of the conserved motif of YxxΦEKVHVQ can prematurely truncate the S protein and reduce the pathogenicity in piglets, which clarifies the effect of the conserved motif of the S protein on virulence.

The S protein is not the only factor affecting viral virulence; ORF3 also plays a role in enhancing viral virulence. In contrast to the BJ2011C strain infected with a severe phenotype, the CHM2013-SBJ strain with a 70–aa deletion in ORF3 did not have any pathogenic properties during infection, underscoring the role of ORF3 in conferring virulence. Similarly, the attenuated DR13 strain lacks 16 amino acids in the ORF3 gene, making it a candidate vaccine against PEDV infection. However, not all ORF3 truncations are effective in reducing pathogenicity; the strains P55, 17GXCZ-1ORF3d and HN2021 with field naturally truncated ORF3 were all lethally virulent compared to field isolates with intact ORF3. Of course, the field strains CHM2013, SM98, and AVCT12 in which 10 amino acids were deleted continuously from the start codon resulting in a full-length truncation of ORF3, had mild phenotypes. These could be explained by the fact that in field isolates, only the complete truncated full-length ORF3 strain may contribute to the reduction of pathogenicity. It has been shown that ORF3 enhances virus production through ion channel activity. A mutation at residue 170 of ORF3 (Y170A) can significantly reduce its ionic activity, which may suggest that the Y170A mutation can be considered one of the targets for reducing virulence.

Studies have shown that the nonstructural protein nsp16, a 2′-O-methyltransferase (2′-O-MTase), also partially attenuates the pathogenicity of severe acute respiratory syndrome coronavirus (SARS-CoV), and may be another important cofactor affecting virus virulence. Studies have confirmed that the attenuated KDKE4A-SYA mutant was constructed by inactivating 2′-O-MTase activity with quadruple alanine substitutions (K45A-D129A-K169A-E202A) and inactivating the endocytic signal of the S protein with mutation (Y1378A), which is a new candidate for live attenuated vaccines.

2.2. Sequence Heterogeneity of S, ORF3, E, M, and N Genes

The availability of attenuated vaccine strains is a major concern, due to the extensive genetic diversity of PEDV strains. To comprehensively study the genetic diversity of PEDV, here, we describe the contribution of each viral protein to the genetic diversity of PEDV from the perspective of viral genome conservation.

The study showed that in 28 Korean field samples, M (0–4%), ORF3 (0–3.9%), and E (0–5.3%) were more conservative than S (0.1–8.4%) and N (0.1–6.8%). Another report pointed out that compared with nsps, M, and N proteins, structural proteins S, and E, and accessory proteins ORF3 were subjected to higher mutational pressure and could generate mutations as high as 57.1% to 71.4%. The M and N proteins, on the other hand, have a higher degree of conservation and are not mutated.

In general, the structural protein S is recognized as the most genetically diverse protein with the highest mutation frequency, and the S gene is often used to construct a phylogenetic tree to study the evolutionary relationship between virus strains. Firstly, the state of S protein N-linked glycosylation may affect viral replication and cellular tropism of viral pathogens. The S1 N-terminal region is the region with the largest number of amino acid variations. Variations in this region may lead to the generation or elimination of potential N-glycosylation sites. It is not difficult to see that the N-terminal region of the S protein may be an important area in which to study the genetic correlation between virus strains. The glycosylation site at residue 725 of the S protein is also a common site of frequent loss, and its function is still unknown. Secondly, variation in the N-linked glycosylation site of the S protein may affect the antigenicity of PEDV. The S protein epitope SS2 (748YSNIGVCK755) and epitope 2C10 (1368GPRLQPY1374), which can induce neutralizing antibodies against PEDV, were conserved in all the Chinese field strains. However, the epitopes COE (aa 499–638) and SS6 (764LQDGQVKI771) show diversity in most field strains and are mutation-prone areas in the epitope regions. Variations on the epitopes COE and SS6 of the S gene may be important references for the development of attenuated vaccines.

ORF3 and S genes have the most insertions and deletions of nucleotide fragments, and may be the two most heterogeneous structures. Much of the focus has been on ORF3 insertions or deletions, and the effects of mutations in ORF3 on virulence or other properties have rarely been examined. As a controversial accessory protein for virulence, the amino acid variation caused by its nucleotide mutation may be more related to the adaptability of the growth environment.

The E protein, like the S, is a cellular marker of PEDV growth adaptation and virulence attenuation. However, genetic and phylogenetic analyses of the E gene have been rarely performed. Except for the attenuated DR13, the E gene of all Chinese PEDV strains has very high conservation. So far, no relevant studies have verified the function of the E protein in virus virulence.

The M protein is involved in the viral envelope, and interacts with the virion core, playing an important role in the viral assembly process. The M gene sequence analyses of 31 PEDV isolates obtained in Thailand and of six PEDV isolates obtained in China both showed that there were no insertions and deletions in the entire M gene, and the glycosylation sequence Asn-Phe-Thr (NFT) in the M gene was also highly conserved. The relationship between M gene heterogeneity and virus pathogenicity has not yet been well examined.

The N protein is an important component of phylogenetic analysis, involved in packaging the viral genome to facilitate viral assembly. The N gene is also highly conserved; none of the early Chinese isolates and the 15 Chinese field samples had insertions or deletions in the N gene, and the N-terminal part of the protein was more conserved than the C-terminal part. PEDV strains with mutations in the N gene may evade the established host immune responses, enhancing the growth adaptability of the virus itself.

2.3. Potential Key Amino Acids

As a key protein that determines the virulence of PEDV, when the attenuated strain does not produce representative variants of deletion or insertion, the effect of S gene mutations on virus virulence and growth adaptability is particularly important, and cannot be ignored. On the one hand, mutations in the S gene may impair the recognition of porcine receptors and reduce the replication effect of PEDV in vivo. On the other hand, mutation of the S gene may be a positive selection, leading to differences in its immunogenicity, which in turn diversifies the neutralization profiles of the virus. To find functional amino acid sites that may be closely related to virus pathogenicity and growth fitness, in Table 3, we summarize the amino acid mutations accumulated in five cell-adapted attenuated strains and one field attenuated strain.

In these PEDV strains, several potentially important amino acid mutations have been elucidated in a review. Amino acid mutations with different properties accumulate in the virus strains with an increasing number of passages, while the mutational spectrum is stable over time, which may increase the stability of the virus in the host. The accumulation of amino acid substitutions is accompanied by drastic changes in amino acid properties, especially mutations in the S1 subunit of the S protein, more than 93.3% of which result in transitions between hydrophilic and hydrophobic amino acids and changes in the charged properties of amino acids. However, the number of these transitions between hydrophilic and hydrophobic amino acids is essentially symmetrical in each strain, which may maintain the biochemical stability of viral proteins. As previously mentioned, the S1 subunit of the S protein is an important factor in determining PEDV virulence. The PC220A-P120, PT-P96, YN144, FJzz1-F200, and OH851 strains were all mutated at domain 0 of the S1 subunit, which has the effect of binding sialic acid receptors on host cells to attach to virions. Mutations in this domain may disrupt binding to sialic glycans and thereby reduce PEDV entry. The domains S A, S B, and S CD of the S1 subunit of the S protein have many B-cell epitopes that induce neutralizing antibodies, and mutations in these domains may affect the recognition of neutralizing antibodies. Especially in the CT-P120 and PT-P96 strains, the F636R and F636S mutations on the epitope COE are likely to reduce the reactivity of virus-neutralizing (VN) antibodies. The S2 subunit, which contains major immunodominant neutralizing epitopes, has a higher mutation frequency than the S1 subunit. More than 63% of mutations in the S protein occur in the S2 subunit. However, the mutations in the S2 subunit are milder. In YN144, PC22A-P120, and CT-P120 strains, 50–60% of the amino acid mutations did not change their biochemical properties, and the rest were changed in respect to charge properties. In PT-P96 and FJZZ1-F200 strains, there are still 85% of amino acid mutations with drastic changes in amino acid properties (charged, hydrophilic or hydrophobic), which may tolerate higher mutation pressure. Frequent mutations on the S2 subunit may be the main reason for the failure of neutralizing antibodies. Taken together, the attenuated virulence of these strains may be due to mutations in the S gene that impair the ability of receptor recognition and binding.

Studies have reported that trypsin can promote cell fusion and viral infection by cleaving the S protein. Efficient viral infection of strains that result in enhanced cellular adaptability through serial passaging is generally more dependent on the presence of trypsin, and mutations in the S2 subunit can control the trypsin dependence of PEDV. In these cell-adapted strains, mutations in the S2 subunit may be closely related to cleavage by trypsin. It has been confirmed that the S888R (R885) mutation may promote the cellular adaptation of the virus by adding a new trypsin cleavage site. Since trypsin cleaves only at arginine and lysine residues, we can speculate that the 888–889SG →RR, F1015L, K1027R, V1242L, and I1305L mutations in these strains might increase trypsin cleavage, to promote the cellular adaptation of PEDV. In addition, common mutations in these attenuated strains may also be a marker of cellular adaptation. From Table 3, we can see that the variant at residue 144 of domain 0, the D265A substitution in domain S A, and the S888R and C1355F substitutions in the S2 subunit, all have higher mutation frequencies, which may be closely related to cell adaptability.

Unlike those cell-adapted strains, amino acid variations on the field strain OH851 were more associated with virulence. Piglets infected with the new variant OH851 with insertions and deletions in the S gene exhibited few or no clinical symptoms. The field variant strain GER/L00719/2014 found in Germany and Portugal, although 99.5% similar to the American OH851 strain, had typical severe watery diarrhea symptoms and high mortality. Sequence alignment revealed that changes in clinical pathogenicity may be due to the variations in key amino acids that affect virulence. Compared with cell-adapted strains, the variation in the field strain OH851 deserves more attention, because it is a likely target for the development of attenuated vaccines.

3. Virus-Host Interaction

PEDV prefers to infect and replicate in the swine intestinal tract, including the villous epithelial cells of the small intestine and jejunum, and the surface epithelial cells of the caecum and colon, of which the jejunum and ileum are the main sites of infection. Infection with PEDV promotes fusion between cells, leading to continuous necrosis of cells, resulting in severe diarrhea and even death in piglets. At the same time, PEDV is sensitive to the porcine liver, resulting in abnormal cholesterol metabolism genes, and disrupting the metabolic homeostasis of cholesterol.

A comprehensive understanding of the infection mechanism by which PEDV invades host cells and achieves replication has important implications for the prevention and control of viral infection. Firstly, PEDV relies on serine proteolysis and low pH to enter cells through endocytosis, which is the entry mechanism by which PEDV infects the host. Secondly, PEDV mainly utilizes viral components to evade the host’s innate immune responses during host infection. It is well known that after the virus invades the host cells, interferon (IFN) plays an important role as a key signaling molecule to block virus infection, especially type I IFNs, which clear the virus by activating various immune cells and costimulatory molecules.

To better understand the biopathogenesis of PED, here, we map the network of PEDV-host interactions (Figure 3), and further elucidate the roles of PEDV components during viral infection. Moreover, host factors, especially functional receptors, may be potential antiviral targets for the effective control and elimination of PEDV. Here, we extend the map of pro/anti-viral host factors of PEDV and summarize the roles of the host factors during PEDV infection (Figure 4).

3.1. PEDV Proteins That Interact with Host Factors

Cell entry of the coronaviruses mainly depends on the interaction of the S protein with the receptor. The cleavage and activation of the S protein may depend on the hydrolysis of S protein by serine proteases at the S1/S2 junction and adjacent to the fusion peptide in the S2 region, during the virus entry process. The S protein enhances TfR1 internalization by interacting with the extracellular domain of TfR1, facilitating viral entry. The S1 subunit of the structural protein S is a key region for the recognition and binding of cellular receptors. Both the C-terminal domain (S1-CTD) and N-terminal domain (S1-NTD) of the S1 subunit of coronaviruses can interact with receptors as RBDs. In a variety of coronaviruses, S1-CTD recognizes and binds to the angiotensin converting enzyme 2 (ACE2), dipeptidyl peptidase 4 (DPP4), and aminopeptidase N (APN) to mediate the entry of SARS-CoV, human coronavirus NL63 (HCoV-NL63), Middle East respiratory syndrome coronavirus (MERS-CoV), transmissible gastroenteritis virus (TGEV) and porcine respiratory coronavirus (PRCV). Meanwhile, S1-NTD, as RBDs, interacts more with the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) or sugar receptors to promote the attachment and entry of viruses such as mouse hepatitis virus (MHV) and bovine coronavirus (BCoV). Similar to other coronaviruses, the RBDs of the receptor pAPN are located within the S1-CTD of PEDV, while the S1-NTD of PEDV is considered to be the RBDs of sialic acid glycans. One study showed that the S protein inhibits IFN-mediated innate immune responses by binding to the epidermal growth factor receptor (EGFR) to increase PEDV infection. As a transmembrane glycoprotein, EGFR may bind to S1-CTD, to promote virus entry, but the RBDs of the S protein that interacts with it remain to be verified.

The E and M proteins inhibit type I IFN immune responses by directly interacting with IRF3 and IFN regulatory factor 7 (IRF7), respectively. In addition to evading innate immune responses, the E protein induces endoplasmic reticulum (ER) stress, upregulates IL-8 expression, and may play a role in inhibiting host-cell apoptosis. It has been confirmed that the M protein interacts with five proteins (RIG-I, PPID, NHE-RF1, S100A11, CLDN4), among which the M protein may inhibit the proliferation of PEDV by interacting with S100A11 or PPID.

The structural protein N plays an important role in promoting viral replication and anti-innate immune responses. In TGEV, the N protein is not essential for RNA replication but is a key protein required for transcription. While the role of PEDV N protein in RNA synthesis has not been elucidated, there has been a lot of indirect evidence for the role of N in PEDV replication. One piece of evidence is that the N protein colocalizes and interacts with nucleophospholipid (NPM1) in the nucleolus, promoting viral replication and inhibiting the apoptotic capacity of cells. Similarly, the interaction of the N protein with p53 promotes viral replication mainly by inducing arrest in the S phase of the cell cycle. Another piece of evidence is that the N protein interacts with heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RNA-binding protein involved in pre-mRNA splicing and mRNA nucleo-cytoplasmic export in the nucleus, promoting PEDV replication. In addition, the PEDV N protein has many mechanisms to evade the host immune responses, one of which is the most classical anti-IFN immune response: the N protein antagonizes the production of IFN-λ3 by blocking the nuclear translocation of NF-κB; the N protein targets TANK-binding kinase 1 (TBK1) through direct interaction, which competitively inhibits the binding of TBK1 to IRF3, resulting in the inhibition of IRF3 activation and the subsequent production of type I IFN. Another novel mechanism for evading host immune responses is the inhibition of HDAC1, an important regulator of innate immunity: the N protein in the nucleus interacts directly with Sp1, an important transcriptional regulator of histone deacetylase (HDAC) expression, indirectly inhibits the replication and transcription of multiple innate immune effectors regulated by HDAC1.

ORF3 is mainly localized in the ER and triggers ER stress responses related to apoptosis or autophagy. Accumulation of ORF3 is also found in the Golgi apparatus (Golgi), which is transported from the ER to the Golgi region via the exocytosis pathway. We also found the presence of ORF3 on the surface of infected cells, and interacting with the S protein at the plasma membrane, which may be related to the ability to regulate viral replication, where the 170YLAI173 motif in the C-terminal part of ORF3 protein is crucial for the transport of ORF3 from the ER to the plasma membrane. ORF3 inhibits NF-κB activation by inhibiting the phosphorylation and expression of nuclear factor P65 and interfering with the nuclear translocation of P65, thereby reducing the production of proinflammatory cytokines IL-6 and IL-8. Meanwhile, ORF3 interacts with IκB kinase β (IKBKB), induces IKBKB-mediated NF-κB promoter activity, and activates type I IFN induction, but inhibits Poly I: C mediated type I IFN production and induction. These findings highlight the complex role of ORF3 in immune signaling and virus–host interactions.

The nonstructural proteins nsps encoded by ORF1a/b have distinct anti-host immune responses, possibly regulating viral replication by enhancing the translation of downstream ORFs. Among them, nsp1 is the most potent suppressor of proinflammatory cytokines, interfering with IFN-induced immune processes. Unlike the E protein interfering with IRF3 nuclear translocation, nsp1 does not interfere with IRF3 phosphorylation and nuclear translocation, but blocks the assembly of IRF3 and CREB-binding protein (CBP) enhanceosome by degrading CBP to suppress the innate immune responses of type I IFN. Besides this, nsp1 also interferes with the nuclear translocation of interferon regulatory factor 1 (IRF1), and suppresses IRF1-mediated type III IFN immune responses. The nsp2 acts through a novel mechanism of non-IFN-mediated host immune responses, which interacts with the innate antiviral factor FBXW7 and hinders the activation of the host innate antiviral response by targeting the ubiquitin-proteasome-mediated degradation of FBXW7. Interestingly, nsp4 is involved in the inflammatory response of the host, directing the expression of proinflammatory cytokines and chemokines, possibly inhibiting PEDV replication in vitro. PEDV nsp5, encoding 3C-like protease, is another IFN antagonist as well as the N protein. Consistent with the foot-and-mouth disease virus (FMDV), hepatitis A virus (HAV), and PRRSV, PEDV nsp5 cleaves the NF-kappaB essential modulator (NEMO), disrupting type I IFN signaling. The nsp6 induces autophagy through the PI3K/Akt/mTOR signaling pathway and has a similar function to its downstream nsp9 in promoting PEDV replication. During PEDV infection, PEDV degrades the signal transducer and activator of transcription 1 (STAT1) proteins in a protease-dependent manner, to interfere with the type I IFN signaling pathway. However, the functional protein of PEDV that degrades STAT1 remains unclear. There is only limited evidence that nsp7 is related to STAT1, and nsp7 can interact with the DNA-binding domains of STAT1/STAT2, blocking the nuclear translocation of STAT1, and further antagonizing IFN-α-induced JAK-STAT signaling. In addition, nsp12, an RNA-dependent RNA polymerase, and nsp13, a helicase, participate in the replication process of PEDV by promoting the release of viral RNA. The G-N-7 methyltransferase (G-N-7 MTase) activity of PEDV nsp14 plays an important role in regulating PEDV replication and type I and type III IFN immune responses. Unlike the N protein sequestered binding of TBK1 and IRF3, nsp15 utilizes endoribonuclease (EndoU) activity to degrade the RNA of TBK1 and IRF3, to inhibit their mediated type I IFN response. The three residues (H226, H241, and K282) of nsp15 that affect the activity of EndoU may be the key amino acids for the inhibition of the antiviral activity. The methyltransferase nsp16 is a more potent regulator of immune-related genes, which relies on KDKE tetrad to regulate the 2′-O-MTase activity, not only reducing IFN-β production but also inhibiting IRF3 phosphorylation, effectively modulating the host antiviral response to multiple viruses including PRRSV, vesicular stomatitis virus (VSV), and PEDV.

Collectively, each protein component of PEDV plays an important role in enhancing viral replication and assembly and evading the host’s innate immune responses. In the case of some nonstructural proteins, such as nsp1, nsp5, nsp6, and nsp13–16, although their roles in evading innate immune signaling have been elucidated, whether they interact with host chaperones remains to be investigated. The analysis of interacting proteins may be important for the elucidation of the molecular mechanisms that promote viral proliferation and evade host immune responses.

3.2. Proviral Host Factor

Host factors required for coronavirus replication are the main targets of antiviral drugs, especially pan-coronavirus host factors. Unraveling the host factors required for coronavirus to infect cells is critical to the development of antiviral drugs.

Each coronavirus has individual specific functional receptors. However, due to limitations such as frequent variants of PEDV and the lack of susceptible host cell lines, especially porcine-derived ones, the research on the infection mechanism of the PEDV virus and the mining of functional host factors have become difficult. difficult. In the process of infecting the host, the virus usually utilizes the components of the host cell to promote the entry, replication, and assembly of the virus, which we generally refer to as proviral host factors. Proviral-host factor inhibitors have also been a commonly used means of antiviral therapy. In Table 4, we summarize the proviral host factors of PEDV and their important functions during virus infection, and describe their mechanism of proviral effect in host cells.

APN (CD13) is an ectoenzyme with membrane binding and signaling functions and is a functional receptor for various coronaviruses such as human coronavirus 229E (HCoV-229E) and TGEV. Porcine APN (pAPN) is a functional receptor of PEDV, and PEDV S1-NTD-CTD can effectively bind to domain VII of pAPN for entry into the host cells. However, recent studies have found that APN is not essential for PEDV entry into cells, and the claim that pAPN acts as a functional receptor for PEDV is inaccurate. The increased susceptibility of pAPN transgenic mice to PEDV may be explained by pAPN promoting PEDV infection through its protease activity.

Sialic acid (SA), mainly the terminal component of glycoproteins and glycolipids, a monosaccharide derivative, exists on the cell surface and is a cofactor for viral attachment and entry into cells. There are three forms of SA commonly found in mammals: 5-N-acetylneuraminic acid (Neu5Ac), 5-N-glycolylneuraminic acid (Neu5Gc) and 2-keto-deoxynonulosonic acid (Kdn). Sialylglycans are the functional receptors for influenza viruses such as avian and human infectious bronchitis coronavirus (IBV) and influenza A virus (IAV), but avian and human influenza viruses generally have different SA binding preferences. SA facilitates the infection of multiple coronaviruses, among which MERS-CoV and TGEV preferentially bind Neu5Ac. PEDV as betacoronaviruses (β-CoVs) also utilizes Neu5Ac as a sugar receptor. However, the binding ability of S protein to SA varies with PEDV strains.

Tight junction (TJ) proteins are multiprotein complexes formed by several different integral membrane proteins. A variety of viruses use components of the TJ proteins as receptors to enter host cells through internalization pathways, including the coxsackie and adenovirus receptors (CAR) and the human occludin receptor. The TJ protein occludin plays an important role in maintaining and repairing the intestinal mucosal barrier. Recently, studies have shown that occludin is not effective at the attachment of PEDV, but occludin acts as a cofactor for PEDV entry into host cells, whose internalization is closely related to virus entry.

Nucleolar phosphoprotein nucleophosmin 1 (NPM1), which predominantly resides in the nucleolus, is a multifunctional protein that plays an important role in RNA transcription, ribosome assembly, DNA replication and repair, nuclear export, and cell growth regulation. NPM1 promotes infection by a variety of viruses, including the human immunodeficiency virus type 1 (HIV-1), Japanese encephalitis virus (JEV), adenovirus, herpes simplex virus 1 (HSV-1), Epstein–Barr Virus (EBV), and Schmallenberg virus (SBV), function at all stages of viral infection. As a proviral factor, NPM1 binds to the cap proteins of porcine circovirus types 2 and 3 (PCV2 and PCV3) to promote nucleolar localization and viral replication. However, there is also evidence for NPM1 as an antiviral factor that limits the replication of the chikungunya virus (CHIKV). NPM1 binds to the N protein of PEDV and colocalizes in the nucleolus, ultimately promoting viral replication mainly by enhancing cell growth and survival. The binding of NPM1 to other proteins of PEDV and its role in viral infection remains to be further explored.

Heat shock protein 70 (HSP70) is involved in the posttranslational folding of the protein, membrane protein localization, assembly and disassembly of the protein complex, and promotes viral replication during RNA virus infection. HSP70 plays a proviral role by binding to the M protein during PEDV infection. However, Hsp70 exerts antiviral effects by inhibiting the nuclear export of the influenza virus ribonucleoprotein complex (vRNP) and the replication process of VSV infection. HSP70 has positive and negative dual regulatory roles on different virus types, showing the complexity of virus-chaperone protein interactions.

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that acts as a cofactor for viral entry into the host cells during hepatitis C virus (HCV), TGEV, and IAV infection. EGFR signaling is a central pathway required for SARS-CoV-2 replication, and EGFR inhibition has emerged as a novel strategy to suppress endogenous antiviral defenses during host infection by respiratory viruses and PEDV. However, at what stage EGFR plays a role in PEDV infection of host cells, has not been elucidated.

3.3. Antiviral Host Factor

In addition to host factors with proviral effects, some host factors resist the invasion of viruses by conferring protection on cells against virus infection, which are generally called antiviral host factors. Antiviral factors are positive regulators of the host’s innate immune system, and become potential targets for antiviral therapy. In Table 4, we summarize the antiviral host factors of PEDV and describe their antiviral effects in host cells.

Bone marrow stromal cell antigen 2 (BST2), also known as CD317, is an IFN-induced type II transmembrane glycoprotein. BST2 inhibits the release of a large number of enveloped viruses, such as human HCoV-229E, human HCV, Dengue virus (DENV), JEV, HIV, Ebola virus, Marburg virus (MARV) and Lassa virus (LASV), HSV-1, human cytomegalovirus (HCMV) and other types of viruses. Studies have shown that BST2 combines with PEDV N protein to achieve protein degradation, thereby inhibiting the biological function of the N protein, while the role of BST2 in viral envelope release has not been elucidated.

Vacuolar Protein Sorting Associated Proteins 36 (VPS36) together with Vps22 and Vps25 form the ESCRT (Endosomal Sorting Complexes Required for Transport)-II complex, which plays a role in the multivesicular body (MVB) pathway of protein sorting and degradation, leading to the degradation of proteins in lysosomes. VPS16 and VPS35 of the VPS family promote the infection of human coronavirus OC43 (HCoV-OC43), HCoV-229E, and SARS-CoV-2 coronaviruses. However, VPS36 was found to interact with ORF3 during PEDV infection, inhibiting PEDV replication by promoting ORF3 degradation. The VPS family may play different roles in the viral infection process.

Cholesterol-25-hydroxylase (CH25H) is a hydroxysterol belonging to the interferon-stimulated gene (ISG) family. CH25H and its enzymatically catalyzed cholesterol product, 25-hydroxycholesterol (25HC), have diverse biological functions, including the regulation of cholesterol metabolism, the dual role of suppressing or increasing inflammation, and the regulation of B- and T-cell-mediated immune responses. CH25H and 25HC also have broad antiviral activity, inhibiting the infection of VSV, rabies virus (RABV), LASV, ZIKV, human rhinovirus (HRV), porcine pseudorabies virus (PRV), and PRRSV through multiple mechanisms. Recent evidence suggests that CH25H and 25HC play an important role in hindering the entry of PEDV virions. As an antiviral factor, CH25H may be an important target for broad-spectrum antiviral therapy.

Ras-GTPase-activating protein-binding protein 1 (G3BP1) is a multifunctional RNA-binding protein involved in various biological functions such as RNA recognition, mRNA turnover and translation, cell proliferation, apoptosis, and differentiation. G3BP1 is also a key component in the assembly of SGs. In response to stimuli, host cells form stress granules (SGs) to prevent viral protein synthesis and regulate viral replication. SGs are more antiviral, and a variety of viruses including many RNA viruses, enteroviruses, coronaviruses, influenza viruses, and reoviruses, possibly inhibit the formation of SGs by cleaving G3BP1 or disrupting the eIF4GI-G3BP1 interaction. Similarly, G3BP1 has an antiviral role in PEDV infection, and PEDV promotes viral replication by inducing the degradation of G3BP1. however, CHIKV of the alphavirus genus has evolved a different mechanism to promote efficient replication by utilizing the SGs component G3BP1. Overall, G3BP1 functions as an antiviral factor in most viral infections.

The ubiquitin ligase FBXW7 is generally regarded as a tumor suppressor capable of targeting various oncogenic proteins for negative regulation. Endogenous FBXW7 significantly inhibited human HCV replication, and a recent report demonstrated that FBXW7 is an innate antiviral factor. The nonstructural protein nsp2 mediates the degradation of FBXW7 by interacting with FBXW7, ultimately suppressing the host antiviral response. Inhibiting the degradation of FBXW7 protein may be an effective strategy for antiviral therapy.

A disintegrin and metalloprotease 17 (ADAM17/CD156b), a member of the metalloprotease superfamily, is responsible for the cleavage of various cell surface proteins and may play a role after viral initial binding and release. ADAM17 may have dual roles during viral infection. On the one hand, ADAM17 induces the replication of human papillomavirus (HPV) and HIV-1. ADAM17 binds directly to E2 protein and plays a key role in CSFV entry, however regulation of ADAM17 activity does not affect SARS-CoV entry. On the other hand, ADAM17 downregulates the expression of CD163, a functional receptor for PRRSV, and blocks viral entry. ADAM17 also inhibits PEDV infection by regulating APN expression. The mechanism of action of ADAM17 in viral infection requires more research evidence.

The L subunit of human eukaryotic translation initiation factor 3 (eIF3L) is one of the subunits of eukaryotic initiation factor (eIF3), which interacts with other eIF3 subunits and may play a role in increasing the physical stability of eIF3. The other subunit of eIF3, eIF3f, can specifically interfere with the 3′ end processing of mRNA, thereby inhibiting HIV-1 replication. The eIF3L can interact with the M protein of PEDV and significantly inhibit virus replication, but how eIF3L inhibits virus infection remains to be further explored. The eIF3L interacts with the NS5 protein of yellow fever virus (YFV) but has a weak role in inhibiting viral replication. During viral infection, more attention may be paid to the role of eIF3L in viral translation.

Poly(A) Binding Protein Cytoplasmic 4 (PABPC4) is a nuclear-cytoplasmic shuttle protein that interacts with the N protein of PEDV, SARS-CoV-2, MHV, IBV, and PDCoV multiple coronaviruses. PABPC4 may inhibit coronavirus infection by degrading the N protein through the cargo receptor NDP52-mediated selective autophagy. PABPC4 may be a broad anti-coronavirus host factor, which has important implications for the selection of antiviral targets.

CD44 is a transmembrane glycoprotein that plays an important role in cell adhesion, growth factor regulation, and signaling such as RTKs, Met, members of the TGFβ family, CXCL12 and its induced CXCR4. Furthermore, CD44 promotes tumorigenesis as a major cell surface receptor for hyaluronic acid (HA). The presence or absence of CD44 does not affect poliovirus replication, and its role in viral infection has also been overlooked. However, recent studies have shown that CD44 is an antiviral host factor that inhibits PEDV infection by activating NF-κB signaling. Similarly, the Goujon C group identified CD44 as a novel anti-SARS-CoV-2 protein factor with potent activity, which has a certain impact on the infection of other coronaviruses such as HCoV-229E and MERS-CoV. CD44 has broad anti-coronavirus activity, which may restrict viral entry by affecting viral internalization. Similarly, chicken CD44 acts as a cellular receptor for the infectious bursal disease virus (IBDV), promoting IBDV binding and entry in B lymphocytes. However, CD44 has less effect on influenza A virus IAV infection. The complex role of CD44 in viral infection of different families and genera is highlighted.

Interleukin-11 (IL-11) is an inflammatory cytokine that plays an important role in inflammation suppression, anti-apoptosis, epithelial regeneration, and fertility. There is evidence that IL-22 inhibits infection by a variety of viruses, including porcine enteric coronaviruses (PEDV, TGEV), porcine rotavirus (PoRV), human respiratory syncytial virus (RSV), and HIV-1. Both IL-11 and IL-22 promote the inhibition of PEDV by activating the STAT3 signaling pathway, and are two important antiviral factors during viral infection.

Mucin 2 (MUC2) is a protein secreted by goblet cells that constitutes the intestinal mucus layer that protects the intestinal epithelial cells. MUC2 mainly has the function of maintaining the intestinal biological barrier. The expression of MUC2 mRNA was induced in PRRSV infection, which played a role in the maintenance of intestinal integrity. Similarly, in PEDV infection experiments, the role of MUC2 in the antiviral was determined.

In addition to host genes involved in the viral infection process, MicroRNA-221-5p, a non-coding RNA involved in post-transcriptional regulation of genes, can also target the 3′UTR of the viral genome and activate the NF-κB signaling pathway to inhibit the replication of PEDV. Noncoding RNA processing may become a new idea for antiviral therapy.

4. Conclusions and Perspectives

The high morbidity and high mortality that PEDV brings to piglets results in a rapid transmission of PEDV in pig populations, which has brought huge economic losses to the global swine industry. Considering the hazards caused by PEDV, preventive immunization is administered by vaccinating pregnant sows. However, due to the high heterogeneity of PEDV, there are currently no effective and safe vaccines to deal with the threat posed by PEDV. Exploring the genetic variation of PEDV and its virulence changes will help us to have a deeper understanding of PEDV and take more efficient diagnosis and treatment measures, accordingly. Similarly, given the problem that there are no efficient vaccines for PEDV treatment, exploring the pathogenesis of PEDV and mining the host factors that interact with PEDV will help us to find potential therapeutic targets, and then develop new prevention and control strategies. Mining host factors as the candidate targets for antiviral therapy, potentially addresses the challenges posed by PEDV genetic diversity to vaccine development. Based on the current state of research, future research should focus on finding the crucial functional receptor for PEDV or identifying key therapeutic targets, and finally developing alternative strategies to target the host proteins or regulators of immune responses, to control this pandemic.

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    Not in our library10.1128/genomea.00243-12

  40. 40.

    Song D., Chen Y., Peng Q., Huang D., Zhang T., Huang T., Zhang F., Zhou X., Tang Y. Full-Length Genome Sequence of a Variant Porcine Epidemic Diarrhea Virus Strain, CH/GDZQ/2014, Responsible for a Severe Outbreak of Diarrhea in Piglets in Guangdong, China, 2014. Genome Announc. 2014;2:e01239-14.

    Not in our library10.1128/genomea.01239-14

  41. 41.

    Murakami S., Miyazaki A., Takahashi O., Hashizume W., Hase Y., Ohashi S., Suzuki T. Complete Genome Sequence of the Porcine Epidemic Diarrhea Virus Variant Tottori2/JPN/2014. Genome Announc. 2015;3:e00877-15.

    Not in our library10.1128/genomea.00877-15

  42. 42.

    Marthaler D., Jiang Y., Otterson T., Goyal S., Rossow K., Collins J. Complete Genome Sequence of Porcine Epidemic Diarrhea Virus Strain USA/Colorado/2013 from the United States. Genome Announc. 2013;1:e00555-13.

    Not in our library10.1128/genomea.00555-13

  43. 43.
    Pathology of US Porcine Epidemic Diarrhea Virus Strain PC21A in Gnotobiotic Pigs · 2014
    No notice
  44. 44.

    Hou Y., Lin C.M., Yokoyama M., Yount B.L., Marthaler D., Douglas A.L., Ghimire S., Qin Y., Baric R.S., Saif L.J., et al. Deletion of a 197-Amino-Acid Region in the N-Terminal Domain of Spike Protein Attenuates Porcine Epidemic Diarrhea Virus in Piglets. J. Virol. 2017;91:e00555-13.

    Not in our library10.1128/jvi.00227-17

  45. 45.

    Bi J., Zeng S., Xiao S., Chen H., Fang L. Complete genome sequence of porcine epidemic diarrhea virus strain AJ1102 isolated from a suckling piglet with acute diarrhea in China. J. Virol. 2012;86:10910-10911.

    Not in our library10.1128/jvi.01919-12

  46. 46.

    Chen F., Pan Y., Zhang X., Tian X., Wang D., Zhou Q., Song Y., Bi Y. Complete genome sequence of a variant porcine epidemic diarrhea virus strain isolated in China. J. Virol. 2012;86:12448.

    Not in our library10.1128/jvi.02228-12

  47. 47.

    Chen F., Zhu Y., Wu M., Ku X., Ye S., Li Z., Guo X., He Q. Comparative Genomic Analysis of Classical and Variant Virulent Parental/Attenuated Strains of Porcine Epidemic Diarrhea Virus. Viruses. 2015;7:5525-5538.

    Not in our library10.3390/v7102891

  48. 48.

    Pan Y., Tian X., Li W., Zhou Q., Wang D., Bi Y., Chen F., Song Y. Isolation and characterization of a variant porcine epidemic diarrhea virus in China. Virol. J. 2012;9:195.

    Not in our library10.1186/1743-422x-9-195

  49. 49.

    Wei Z.Y., Lu W.H., Li Z.L., Mo J.Y., Zeng X.D., Zeng Z.L., Sun B.L., Chen F., Xie Q.M., Bee Y.Z., et al. Complete genome sequence of novel porcine epidemic diarrhea virus strain GD-1 in China. J. Virol. 2012;86:13824-13825.

    Not in our library10.1128/jvi.02615-12

  50. 50.

    Fan H., Zhang J., Ye Y., Tong T., Xie K., Liao M. Complete genome sequence of a novel porcine epidemic diarrhea virus in south China. J. Virol. 2012;86:10248-10249.

    Not in our library10.1128/jvi.01589-12

  51. 51.
    New Variant of Porcine Epidemic Diarrhea Virus, United States, 2014 · 2014
    No notice
  52. 52.
    Detection and Genetic Characterization of Deltacoronavirus in Pigs, Ohio, USA, 2014 · 2014
    No notice
  53. 53.

    Theuns S., Conceicao-Neto N., Christiaens I., Zeller M., Desmarets L.M., Roukaerts I.D., Acar D.D., Heylen E., Matthijnssens J., Nauwynck H.J. Complete genome sequence of a porcine epidemic diarrhea virus from a novel outbreak in belgium, january 2015. Genome Announc. 2015;3:e00506-15.

    Not in our library10.1128/genomea.00506-15

  54. 54.

    Sun M., Ma J., Wang Y., Wang M., Song W., Zhang W., Lu C., Yao H. Genomic and epidemiological characteristics provide new insights into the phylogeographical and spatiotemporal spread of porcine epidemic diarrhea virus in Asia. J. Clin. Microbiol. 2015;53:1484-1492.

    Not in our library10.1128/jcm.02898-14

  55. 55.

    Kim S.H., Lee J.M., Jung J., Kim I.J., Hyun B.H., Kim H.I., Park C.K., Oem J.K., Kim Y.H., Lee M.H., et al. Genetic characterization of porcine epidemic diarrhea virus in Korea from 1998 to 2013. Arch. Virol. 2015;160:1055-1064.

    Not in our library10.1007/s00705-015-2353-y

  56. 56.

    Masuda T., Murakami S., Takahashi O., Miyazaki A., Ohashi S., Yamasato H., Suzuki T. New porcine epidemic diarrhoea virus variant with a large deletion in the spike gene identified in domestic pigs. Arch. Virol. 2015;160:2565-2568.

    Not in our library10.1007/s00705-015-2522-z

  57. 57.

    Vui D.T., Tung N., Inui K., Slater S., Nilubol D. Complete genome sequence of porcine epidemic diarrhea virus in Vietnam. Genome Announc. 2014;2:e00753-14.

    Not in our library10.1128/genomea.00753-14

  58. 58.

    Cheun-Arom T., Temeeyasen G., Srijangwad A., Tripipat T., Sangmalee S., Vui D.T., Chuanasa T., Tantituvanont A., Nilubol D. Complete Genome Sequences of Two Genetically Distinct Variants of Porcine Epidemic Diarrhea Virus in the Eastern Region of Thailand. Genome Announc. 2015;3:e00634-15.

    Not in our library10.1128/genomea.00634-15

  59. 59.

    Paraguison-Alili R., Domingo C.Y. Phylogenetic tracking of current porcine epidemic diarrhea virus (PEDV) strains in the Philippines. Arch. Virol. 2016;161:2601-2604.

    Not in our library10.1007/s00705-016-2938-0

  60. 60.

    Diep N.V., Sueyoshi M., Izzati U., Fuke N., Teh A.P.P., Lan N.T., Yamaguchi R. Appearance of US-like porcine epidemic diarrhoea virus (PEDV) strains before US outbreaks and genetic heterogeneity of PEDVs collected in Northern Vietnam during 2012-2015. Transbound Emerg. Dis. 2018;65:e83-e93.

    Not in our library10.1111/tbed.12681

  61. 61.

    Huang Y.W., Dickerman A.W., Pineyro P., Li L., Fang L., Kiehne R., Opriessnig T., Meng X.J. Origin, evolution, and genotyping of emergent porcine epidemic diarrhea virus strains in the United States. mBio. 2013;4:e00737-13.

    Not in our library10.1128/mbio.00737-13

  62. 62.

    Ojkic D., Hazlett M., Fairles J., Marom A., Slavic D., Maxie G., Alexandersen S., Pasick J., Alsop J., Burlatschenko S. The first case of porcine epidemic diarrhea in Canada. Can. Vet. J. 2015;56:149-152.

    Not in our library

  63. 63.
    Distinct Characteristics and Complex Evolution of PEDV Strains, North America, May 2013–February 2014 · 2014
    No notice
  64. 64.

    Stadler J., Zoels S., Fux R., Hanke D., Pohlmann A., Blome S., Weissenbock H., Weissenbacher-Lang C., Ritzmann M., Ladinig A. Emergence of porcine epidemic diarrhea virus in southern Germany. BMC Vet. Res. 2015;11:142.

    Not in our library10.1186/s12917-015-0454-1

  65. 65.

    Dortmans J., Li W., van der Wolf P.J., Buter G.J., Franssen P.J.M., van Schaik G., Houben M., Bosch B.J. Porcine epidemic diarrhea virus (PEDV) introduction into a naive Dutch pig population in 2014. Vet. Microbiol. 2018;221:13-18.

    Not in our library10.1016/j.vetmic.2018.05.014

  66. 66.

    Grasland B., Bigault L., Bernard C., Quenault H., Toulouse O., Fablet C., Rose N., Touzain F., Blanchard Y. Complete genome sequence of a porcine epidemic diarrhea s gene indel strain isolated in france in december 2014. Genome Announc. 2015;3:e00535-15.

    Not in our library10.1128/genomea.00535-15

  67. 67.

    Mesquita J.R., Hakze-van der Honing R., Almeida A., Lourenco M., van der Poel W.H., Nascimento M.S. Outbreak of Porcine Epidemic Diarrhea Virus in Portugal, 2015. Transbound Emerg. Dis. 2015;62:586-588.

    Not in our library10.1111/tbed.12409

  68. 68.

    Steinrigl A., Fernandez S.R., Stoiber F., Pikalo J., Sattler T., Schmoll F. First detection, clinical presentation and phylogenetic characterization of Porcine epidemic diarrhea virus in Austria. BMC Vet. Res. 2015;11:310.

    Not in our library10.1186/s12917-015-0624-1

  69. 69.

    Woo P.C., Lau S.K., Lam C.S., Lau C.C., Tsang A.K., Lau J.H., Bai R., Teng J.L., Tsang C.C., Wang M., et al. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J. Virol. 2012;86:3995-4008.

    Not in our library10.1128/jvi.06540-11

  70. 70.

    Kocherhans R., Bridgen A., Ackermann M., Tobler K. Completion of the porcine epidemic diarrhoea coronavirus (PEDV) genome sequence. Virus Genes. 2001;23:137-144.

    Not in our library10.1023/a:1011831902219

  71. 71.

    Shen Z., Yang Y., Yang S., Zhang G., Xiao S., Fu Z.F., Peng G. Structural and Biological Basis of Alphacoronavirus nsp1 Associated with Host Proliferation and Immune Evasion. Viruses. 2020;12:812.

    Not in our library10.3390/v12080812

  72. 72.

    Liu C., Tang J., Ma Y., Liang X., Yang Y., Peng G., Qi Q., Jiang S., Li J., Du L., et al. Receptor usage and cell entry of porcine epidemic diarrhea coronavirus. J. Virol. 2015;89:6121-6125.

    Not in our library10.1128/jvi.00430-15

  73. 73.
    Cellular entry of the porcine epidemic diarrhea virus · 2016
    No notice
  74. 74.

    Su Y., Hou Y., Wang Q. The enhanced replication of an S-intact PEDV during coinfection with an S1 NTD-del PEDV in piglets. Vet. Microbiol. 2019;228:202-212.

    Not in our library10.1016/j.vetmic.2018.11.025

  75. 75.
    Structural Bases of Coronavirus Attachment to Host Aminopeptidase N and Its Inhibition by Neutralizing Antibodies · 2012
    No notice
  76. 76.

    Li Z., Ma Z., Li Y., Gao S., Xiao S. Porcine epidemic diarrhea virus: Molecular mechanisms of attenuation and vaccines. Microb. Pathog. 2020;149:104553.

    Not in our library10.1016/j.micpath.2020.104553

  77. 77.

    Eckert D.M., Kim P.S. Mechanisms of viral membrane fusion and its inhibition. Annu. Rev. Biochem. 2001;70:777-810.

    Not in our library10.1146/annurev.biochem.70.1.777

  78. 78.

    Sun D., Feng L., Shi H., Chen J., Cui X., Chen H., Liu S., Tong Y., Wang Y., Tong G. Identification of two novel B cell epitopes on porcine epidemic diarrhea virus spike protein. Vet. Microbiol. 2008;131:73-81.

    Not in our library10.1016/j.vetmic.2008.02.022

  79. 79.

    Van Diep N., Choijookhuu N., Fuke N., Myint O., Izzati U.Z., Suwanruengsri M., Hishikawa Y., Yamaguchi R. New tropisms of porcine epidemic diarrhoea virus (PEDV) in pigs naturally coinfected by variants bearing large deletions in the spike (S) protein and PEDVs possessing an intact S protein. Transbound Emerg. Dis. 2020;67:2589-2601.

    Not in our library10.1111/tbed.13607

  80. 80.

    Liu C., Ma Y., Yang Y., Zheng Y., Shang J., Zhou Y., Jiang S., Du L., Li J., Li F. Cell Entry of Porcine Epidemic Diarrhea Coronavirus Is Activated by Lysosomal Proteases. J. Biol. Chem. 2016;291:24779-24786.

    Not in our library10.1074/jbc.m116.740746

  81. 81.

    Lee D.K., Park C.K., Kim S.H., Lee C. Heterogeneity in spike protein genes of porcine epidemic diarrhea viruses isolated in Korea. Virus Res. 2010;149:175-182.

    Not in our library10.1016/j.virusres.2010.01.015

  82. 82.

    Wicht O., Li W., Willems L., Meuleman T.J., Wubbolts R.W., van Kuppeveld F.J., Rottier P.J., Bosch B.J. Proteolytic activation of the porcine epidemic diarrhea coronavirus spike fusion protein by trypsin in cell culture. J. Virol. 2014;88:7952-7961.

    Not in our library10.1128/jvi.00297-14

  83. 83.

    Jantraphakorn Y., Viriyakitkosol R., Jongkaewwattana A., Kaewborisuth C. Interaction Between PEDV and Its Hosts: A Closer Look at the ORF3 Accessory Protein. Front. Vet. Sci. 2021;8:744276.

    Not in our library10.3389/fvets.2021.744276

  84. 84.

    Wang K., Lu W., Chen J., Xie S., Shi H., Hsu H., Yu W., Xu K., Bian C., Fischer W.B., et al. PEDV ORF3 encodes an ion channel protein and regulates virus production. FEBS Lett. 2012;586:384-391.

    Not in our library10.1016/j.febslet.2012.01.005

  85. 85.

    Lu W., Zheng B.J., Xu K., Schwarz W., Du L., Wong C.K., Chen J., Duan S., Deubel V., Sun B. Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proc. Natl. Acad. Sci. USA. 2006;103:12540-12545.

    Not in our library10.1073/pnas.0605402103

  86. 86.

    Ye S., Li Z., Chen F., Li W., Guo X., Hu H., He Q. Porcine epidemic diarrhea virus ORF3 gene prolongs S-phase, facilitates formation of vesicles and promotes the proliferation of attenuated PEDV. Virus Genes. 2015;51:385-392.

    Not in our library10.1007/s11262-015-1257-y

  87. 87.
    Porcine epidemic diarrhea virus E protein causes endoplasmic reticulum stress and up-regulates interleukin-8 expression · 2013
    Not checked
  88. 88.

    Torres J., Maheswari U., Parthasarathy K., Ng L., Liu D.X., Gong X. Conductance and amantadine binding of a pore formed by a lysine-flanked transmembrane domain of SARS coronavirus envelope protein. Protein Sci. 2007;16:2065-2071.

    Not in our library10.1110/ps.062730007

  89. 89.

    Zheng L., Wang X., Guo D., Cao J., Cheng L., Li X., Zou D., Zhang Y., Xu J., Wu X., et al. Porcine epidemic diarrhea virus E protein suppresses RIG-I signaling-mediated interferon-beta production. Vet. Microbiol. 2021;254:108994.

    Not in our library10.1016/j.vetmic.2021.108994

  90. 90.

    Vennema H., Godeke G.J., Rossen J.W., Voorhout W.F., Horzinek M.C., Opstelten D.J., Rottier P.J. Nucleocapsid-independent assembly of coronavirus-like particles by co-expression of viral envelope protein genes. EMBO J. 1996;15:2020-2028.

    Not in our library10.1002/j.1460-2075.1996.tb00553.x

  91. 91.

    Fischer F., Stegen C.F., Masters P.S., Samsonoff W.A. Analysis of constructed E gene mutants of mouse hepatitis virus confirms a pivotal role for E protein in coronavirus assembly. J. Virol. 1998;72:7885-7894.

    Not in our library10.1128/jvi.72.10.7885-7894.1998

  92. 92.

    Raamsman M.J., Locker J.K., de Hooge A., de Vries A.A., Griffiths G., Vennema H., Rottier P.J. Characterization of the coronavirus mouse hepatitis virus strain A59 small membrane protein E. J. Virol. 2000;74:2333-2342.

    Not in our library10.1128/jvi.74.5.2333-2342.2000

  93. 93.

    Nguyen V.P., Hogue B.G. Protein interactions during coronavirus assembly. J. Virol. 1997;71:9278-9284.

    Not in our library10.1128/jvi.71.12.9278-9284.1997

  94. 94.

    De Haan C.A., Kuo L., Masters P.S., Vennema H., Rottier P.J. Coronavirus particle assembly: Primary structure requirements of the membrane protein. J. Virol. 1998;72:6838-6850.

    Not in our library10.1128/jvi.72.8.6838-6850.1998

  95. 95.

    Vennema H., de Groot R.J., Harbour D.A., Horzinek M.C., Spaan W.J. Primary structure of the membrane and nucleocapsid protein genes of feline infectious peritonitis virus and immunogenicity of recombinant vaccinia viruses in kittens. Virology. 1991;181:327-335.

    Not in our library10.1016/0042-6822(91)90499-2

  96. 96.

    Woods R.D., Wesley R.D., Kapke P.A. Neutralization of porcine transmissible gastroenteritis virus by complement-dependent monoclonal antibodies. Am. J. Vet. Res. 1988;49:300-304.

    Not in our library

  97. 97.

    Zhang Q., Shi K., Yoo D. Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1. Virology. 2016;489:252-268.

    Not in our library10.1016/j.virol.2015.12.010

  98. 98.

    Xu X.G., Zhang H.L., Zhang Q., Dong J., Huang Y., Tong D.W. Porcine epidemic diarrhea virus M protein blocks cell cycle progression at S-phase and its subcellular localization in the porcine intestinal epithelial cells. Acta. Virol. 2015;59:265-275.

    Not in our library10.4149/av_2015_03_265

  99. 99.
    The Coronavirus Nucleocapsid Is a Multifunctional Protein · 2014
    No notice
  100. 100.

    Zuniga S., Cruz J.L., Sola I., Mateos-Gomez P.A., Palacio L., Enjuanes L. Coronavirus nucleocapsid protein facilitates template switching and is required for efficient transcription. J. Virol. 2010;84:2169-2175.

    Not in our library10.1128/jvi.02011-09

  101. 101.

    Hurst K.R., Ye R., Goebel S.J., Jayaraman P., Masters P.S. An interaction between the nucleocapsid protein and a component of the replicase-transcriptase complex is crucial for the infectivity of coronavirus genomic RNA. J. Virol. 2010;84:10276-10288.

    Not in our library10.1128/jvi.01287-10

  102. 102.

    Ding Z., Fang L., Jing H., Zeng S., Wang D., Liu L., Zhang H., Luo R., Chen H., Xiao S. Porcine epidemic diarrhea virus nucleocapsid protein antagonizes beta interferon production by sequestering the interaction between IRF3 and TBK1. J. Virol. 2014;88:8936-8945.

    Not in our library10.1128/jvi.00700-14

  103. 103.

    Xu X., Zhang H., Zhang Q., Huang Y., Dong J., Liang Y., Liu H.J., Tong D. Porcine epidemic diarrhea virus N protein prolongs S-phase cell cycle, induces endoplasmic reticulum stress, and up-regulates interleukin-8 expression. Vet. Microbiol. 2013;164:212-221.

    Not in our library10.1016/j.vetmic.2013.01.034

  104. 104.

    Shi D., Shi H., Sun D., Chen J., Zhang X., Wang X., Zhang J., Ji Z., Liu J., Cao L., et al. Nucleocapsid Interacts with NPM1 and Protects it from Proteolytic Cleavage, Enhancing Cell Survival, and is Involved in PEDV Growth. Sci. Rep. 2017;7:39700.

    Not in our library10.1038/srep39700

  105. 105.
    Growth enhancement of porcine epidemic diarrhea virus (PEDV) in Vero E6 cells expressing PEDV nucleocapsid protein. · 2019
    Not checked
  106. 106.

    Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol. 2016;3:237-261.

    Not in our library10.1146/annurev-virology-110615-042301

  107. 107.

    Hofmann H., Hattermann K., Marzi A., Gramberg T., Geier M., Krumbiegel M., Kuate S., Uberla K., Niedrig M., Pohlmann S. S protein of severe acute respiratory syndrome-associated coronavirus mediates entry into hepatoma cell lines and is targeted by neutralizing antibodies in infected patients. J. Virol. 2004;78:6134-6142.

    Not in our library10.1128/jvi.78.12.6134-6142.2004

  108. 108.

    Hulswit R.J., de Haan C.A., Bosch B.J. Coronavirus Spike Protein and Tropism Changes. Adv. Virus Res. 2016;96:29-57.

    Not in our library10.1016/bs.aivir.2016.08.004

  109. 109.

    Hou Y., Ke H., Kim J., Yoo D., Su Y., Boley P., Chepngeno J., Vlasova A.N., Saif L.J., Wang Q. Engineering a Live Attenuated Porcine Epidemic Diarrhea Virus Vaccine Candidate via Inactivation of the Viral 2′-O-Methyltransferase and the Endocytosis Signal of the Spike Protein. J. Virol. 2019;93:e00406-19.

    Not in our library10.1128/jvi.00406-19

  110. 110.

    Chen P., Zhao X., Zhou S., Zhou T., Tan X., Wu X., Tong W., Gao F., Yu L., Jiang Y., et al. A Virulent PEDV Strain FJzz1 with Genomic Mutations and Deletions at the High Passage Level Was Attenuated in Piglets via Serial Passage In Vitro. Virol. Sin. 2021;36:1052-1065.

    Not in our library10.1007/s12250-021-00368-w

  111. 111.

    Chen P., Wang K., Hou Y., Li H., Li X., Yu L., Jiang Y., Gao F., Tong W., Yu H., et al. Genetic evolution analysis and pathogenicity assessment of porcine epidemic diarrhea virus strains circulating in part of China during 2011-2017. Infect. Genet. Evol. 2019;69:153-165.

    Not in our library10.1016/j.meegid.2019.01.022

  112. 112.

    Lin C.M., Annamalai T., Liu X., Gao X., Lu Z., El-Tholoth M., Hu H., Saif L.J., Wang Q. Experimental infection of a US spike-insertion deletion porcine epidemic diarrhea virus in conventional nursing piglets and cross-protection to the original US PEDV infection. Vet. Res. 2015;46:134.

    Not in our library10.1186/s13567-015-0278-9

  113. 113.

    Tsai K.J., Deng M.C., Wang F.I., Tsai S.H., Chang C., Chang C.Y., Huang Y.L. Deletion in the S1 Region of Porcine Epidemic Diarrhea Virus Reduces the Virulence and Influences the Virus-Neutralizing Activity of the Antibody Induced. Viruses. 2020;12:1378.

    Not in our library10.3390/v12121378

  114. 114.

    Hou Y., Meulia T., Gao X., Saif L.J., Wang Q. Deletion of both the Tyrosine-Based Endocytosis Signal and the Endoplasmic Reticulum Retrieval Signal in the Cytoplasmic Tail of Spike Protein Attenuates Porcine Epidemic Diarrhea Virus in Pigs. J. Virol. 2019;93:e01758-18.

    Not in our library10.1128/jvi.01758-18

  115. 115.

    Zhang X., Pan Y., Wang D., Tian X., Song Y., Cao Y. Identification and pathogenicity of a variant porcine epidemic diarrhea virus field strain with reduced virulence. Virol. J. 2015;12:88.

    Not in our library10.1186/s12985-015-0314-4

  116. 116.

    Lee S., Son K.Y., Noh Y.H., Lee S.C., Choi H.W., Yoon I.J., Lee C. Genetic characteristics, pathogenicity, and immunogenicity associated with cell adaptation of a virulent genotype 2b porcine epidemic diarrhea virus. Vet. Microbiol. 2017;207:248-258.

    Not in our library10.1016/j.vetmic.2017.06.019

  117. 117.

    Lu Y., Huang W., Zhong L., Qin Y., Liu X., Yang C., Wang R., Su X., Du C., Mi X., et al. Comparative Characterization and Pathogenicity of a Novel Porcine Epidemic Diarrhea Virus (PEDV) with a Naturally Occurring Truncated ORF3 Gene Coinfected with PEDVs Possessing an Intact ORF3 Gene in Piglets. Viruses. 2021;13:1562.

    Not in our library10.3390/v13081562

  118. 118.

    Zhang Y.H., Li H.X., Chen X.M., Zhang L.H., Zhao Y.Y., Luo A.F., Yang Y.R., Zheng L.L., Chen H.Y. Genetic Characteristics and Pathogenicity of a Novel Porcine Epidemic Diarrhea Virus with a Naturally Occurring Truncated ORF3 Gene. Viruses. 2022;14:487.

    Not in our library10.3390/v14030487

  119. 119.

    Suzuki T., Terada Y., Enjuanes L., Ohashi S., Kamitani W. S1 Subunit of Spike Protein from a Current Highly Virulent Porcine Epidemic Diarrhea Virus Is an Important Determinant of Virulence in Piglets. Viruses. 2018;10:467.

    Not in our library10.3390/v10090467

  120. 120.

    Wang D., Ge X., Chen D., Li J., Cai Y., Deng J., Zhou L., Guo X., Han J., Yang H. The S Gene Is Necessary but Not Sufficient for the Virulence of Porcine Epidemic Diarrhea Virus Novel Variant Strain BJ2011C. J. Virol. 2018;92:e00603-18.

    Not in our library10.1128/jvi.00603-18

  121. 121.

    Song D.S., Yang J.S., Oh J.S., Han J.H., Park B.K. Differentiation of a Vero cell adapted porcine epidemic diarrhea virus from Korean field strains by restriction fragment length polymorphism analysis of ORF 3. Vaccine. 2003;21:1833-1842.

    Not in our library10.1016/s0264-410x(03)00027-6

  122. 122.

    Si F., Chen B., Hu X., Yu R., Dong S., Wang R., Li Z. Porcine Epidemic Diarrhea Virus ORF3 Protein Is Transported through the Exocytic Pathway. J. Virol. 2020;94:e00808-20.

    Not in our library10.1128/jvi.00808-20

  123. 123.

    Menachery V.D., Gralinski L.E., Mitchell H.D., Dinnon K.H., Leist S.R., Yount B.L., McAnarney E.T., Graham R.L., Waters K.M., Baric R.S. Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines. J. Virol. 2018;92:e00710-18.

    Not in our library10.1128/jvi.00710-18

  124. 124.

    Su M., Li C., Qi S., Yang D., Jiang N., Yin B., Guo D., Kong F., Yuan D., Feng L., et al. A molecular epidemiological investigation of PEDV in China: Characterization of co-infection and genetic diversity of S1-based genes. Transbound Emerg. Dis. 2020;67:1129-1140.

    Not in our library10.1111/tbed.13439

  125. 125.

    Li Y., Wang G., Wang J., Man K., Yang Q. Cell attenuated porcine epidemic diarrhea virus strain Zhejiang08 provides effective immune protection attributed to dendritic cell stimulation. Vaccine. 2017;35:7033-7041.

    Not in our library10.1016/j.vaccine.2017.10.052

  126. 126.
    Genetic characterization and phylogenetic analysis of porcine epidemic diarrhea virus in Guangdong, China, between 2018 and 2019. · 2021
    Not checked
  127. 127.

    Tian Y., Yang X., Li H., Ma B., Guan R., Yang J., Chen D., Han X., Zhou L., Song Z., et al. Molecular characterization of porcine epidemic diarrhea virus associated with outbreaks in southwest China during 2014–2018. Transbound Emerg. Dis. 2021;68:3482-3497.

    Not in our library10.1111/tbed.13953

  128. 128.

    Chen X., Zeng L., Yang J., Yu F., Ge J., Guo Q., Gao X., Song T. Sequence heterogeneity of the ORF3 gene of porcine epidemic diarrhea viruses field samples in Fujian, China, 2010—2012. Viruses. 2013;5:2375-2383.

    Not in our library10.3390/v5102375

  129. 129.

    Escors D., Camafeita E., Ortego J., Laude H., Enjuanes L. Organization of two transmissible gastroenteritis coronavirus membrane protein topologies within the virion and core. J. Virol. 2001;75:12228-12240.

    Not in our library10.1128/jvi.75.24.12228-12240.2001

  130. 130.

    Chen J.F., Sun D.B., Wang C.B., Shi H.Y., Cui X.C., Liu S.W., Qiu H.J., Feng L. Molecular characterization and phylogenetic analysis of membrane protein genes of porcine epidemic diarrhea virus isolates in China. Virus Genes. 2008;36:355-364.

    Not in our library10.1007/s11262-007-0196-7

  131. 131.

    Chen J., Liu X., Lang H., Wang Z., Shi D., Shi H., Zhang X., Feng L. Genetic variation of nucleocapsid genes of porcine epidemic diarrhea virus field strains in China. Arch. Virol. 2013;158:1397-1401.

    Not in our library10.1007/s00705-013-1608-8

  132. 132.

    Li Z., Chen F., Yuan Y., Zeng X., Wei Z., Zhu L., Sun B., Xie Q., Cao Y., Xue C., et al. Sequence and phylogenetic analysis of nucleocapsid genes of porcine epidemic diarrhea virus (PEDV) strains in China. Arch. Virol. 2013;158:1267-1273.

    Not in our library10.1007/s00705-012-1592-4

  133. 133.

    Park J.Y., Pak S.I., Sung H.W., Kim J.H., Song C.S., Lee C.W., Kwon H.M. Variations in the nucleocapsid protein gene of infectious bronchitis viruses isolated in Korea. Virus Genes. 2005;31:153-162.

    Not in our library10.1007/s11262-005-1788-8

  134. 134.

    de Haan C.A., Rottier P.J. Molecular interactions in the assembly of coronaviruses. Adv. Virus Res. 2005;64:165-230.

    Not in our library10.1016/s0065-3527(05)64006-7

  135. 135.

    Li F., Zeng Y., Zhang R., Peng K., Jiang C., Xu Z., Zhu L. Genetic variations in S gene of porcine epidemic diarrhoea virus from 2018 in Sichuan Province, China. Vet. Med. Sci. 2020;6:910-918.

    Not in our library10.1002/vms3.326

  136. 136.

    Kim S.J., Nguyen V.G., Huynh T.M., Park Y.H., Park B.K., Chung H.C. Molecular Characterization of Porcine Epidemic Diarrhea Virus and Its New Genetic Classification Based on the Nucleocapsid Gene. Viruses. 2020;12:790.

    Not in our library10.3390/v12080790

  137. 137.

    Hou Y., Wang Q. Emerging Highly Virulent Porcine Epidemic Diarrhea Virus: Molecular Mechanisms of Attenuation and Rational Design of Live Attenuated Vaccines. Int. J. Mol. Sci. 2019;20:5478.

    Not in our library10.3390/ijms20215478

  138. 138.

    Liu J., Shi H., Chen J., Zhang X., Ji Z., Yuan J., Shi D., Cao L., Zhu X., Dong H., et al. Neutralization of genotype 2 porcine epidemic diarrhea virus strains by a novel monoclonal antibody. Virology. 2017;507:257-262.

    Not in our library10.1016/j.virol.2017.04.026

  139. 139.

    Lin C.M., Hou Y., Marthaler D.G., Gao X., Liu X., Zheng L., Saif L.J., Wang Q. Attenuation of an original US porcine epidemic diarrhea virus strain PC22A via serial cell culture passage. Vet. Microbiol. 2017;201:62-71.

    Not in our library10.1016/j.vetmic.2017.01.015

  140. 140.

    Wu Y., Li W., Zhou Q., Li Q., Xu Z., Shen H., Chen F. Characterization and pathogenicity of Vero cell-attenuated porcine epidemic diarrhea virus CT strain. Virol. J. 2019;16:121.

    Not in our library10.1186/s12985-019-1232-7

  141. 141.

    Chang Y.C., Kao C.F., Chang C.Y., Jeng C.R., Tsai P.S., Pang V.F., Chiou H.Y., Peng J.Y., Cheng I.C., Chang H.W. Evaluation and Comparison of the Pathogenicity and Host Immune Responses Induced by a G2b Taiwan Porcine Epidemic Diarrhea Virus (Strain Pintung 52) and Its Highly Cell-Culture Passaged Strain in Conventional 5-Week-Old Pigs. Viruses. 2017;9:121.

    Not in our library10.3390/v9050121

  142. 142.

    Thavorasak T., Chulanetra M., Glab-Ampai K., Teeranitayatarn K., Songserm T., Yodsheewan R., Sae-Lim N., Lekcharoensuk P., Sookrung N., Chaicumpa W. Novel Neutralizing Epitope of PEDV S1 Protein Identified by IgM Monoclonal Antibody. Viruses. 2022;14:125.

    Not in our library10.3390/v14010125

  143. 143.

    Li C., Li W., Lucio de Esesarte E., Guo H., van den Elzen P., Aarts E., van den Born E., Rottier P.J.M., Bosch B.J. Cell Attachment Domains of the Porcine Epidemic Diarrhea Virus Spike Protein Are Key Targets of Neutralizing Antibodies. J. Virol. 2017;91:e00273-17.

    Not in our library10.1128/jvi.00273-17

  144. 144.

    Okda F.A., Lawson S., Singrey A., Nelson J., Hain K.S., Joshi L.R., Christopher-Hennings J., Nelson E.A., Diel D.G. The S2 glycoprotein subunit of porcine epidemic diarrhea virus contains immunodominant neutralizing epitopes. Virology. 2017;509:185-194.

    Not in our library10.1016/j.virol.2017.06.013

  145. 145.

    Park J.E., Cruz D.J., Shin H.J. Receptor-bound porcine epidemic diarrhea virus spike protein cleaved by trypsin induces membrane fusion. Arch. Virol. 2011;156:1749-1756.

    Not in our library10.1007/s00705-011-1044-6

  146. 146.

    Tan Y., Sun L., Wang G., Shi Y., Dong W., Fu Y., Fu Z., Chen H., Peng G. The trypsin-enhanced infection of porcine epidemic diarrhea virus is determined by the S2 subunit of the spike glycoprotein. J. Virol. 2021;95:e02453-e20.

    Not in our library10.1128/jvi.02453-20

  147. 147.

    Belouzard S., Chu V.C., Whittaker G.R. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. USA. 2009;106:5871-5876.

    Not in our library10.1073/pnas.0809524106

  148. 148.

    Ducatelle R., Coussement W., Pensaert M.B., Debouck P., Hoorens J. In vivo morphogenesis of a new porcine enteric coronavirus, CV 777. Arch. Virol. 1981;68:35-44.

    Not in our library10.1007/bf01315165

  149. 149.

    Ducatelle R., Coussement W., Debouck P., Hoorens J. Pathology of experimental CV777 coronavirus enteritis in piglets. II. Electron microscopic study. Vet. Pathol. 1982;19:57-66.

    Not in our library10.1177/030098588201900109

  150. 150.

    Debouck P., Pensaert M., Coussement W. The pathogenesis of an enteric infection in pigs, experimentally induced by the coronavirus-like agent, CV 777. Vet. Microbiol. 1981;6:157-165.

    Not in our library10.1016/0378-1135(81)90007-9

  151. 151.

    Park J.E., Shin H.J. Porcine epidemic diarrhea virus infects and replicates in porcine alveolar macrophages. Virus Res. 2014;191:143-152.

    Not in our library10.1016/j.virusres.2014.07.038

  152. 152.
    Aberrant Cholesterol Metabolic Genes Regulation in a Negative Feedback Loop Induced by an Alphacoronavirus · 2022
    Not checked
  153. 153.

    Park J.E., Cruz D.J., Shin H.J. Clathrin- and serine proteases-dependent uptake of porcine epidemic diarrhea virus into Vero cells. Virus Res. 2014;191:21-29.

    Not in our library10.1016/j.virusres.2014.07.022

  154. 154.

    Isaacs A., Lindenmann J. Virus interference. I. The interferon. Proc. R Soc. Lond. B Biol. Sci. 1957;147:258-267.

    Not in our library10.1098/rspb.1957.0048

  155. 155.

    Raftery N., Stevenson N.J. Advances in anti-viral immune defence: Revealing the importance of the IFN JAK/STAT pathway. Cell Mol. Life Sci. 2017;74:2525-2535.

    Not in our library10.1007/s00018-017-2520-2

  156. 156.

    Yamada Y., Liu D.X. Proteolytic activation of the spike protein at a novel RRRR/S motif is implicated in furin-dependent entry, syncytium formation, and infectivity of coronavirus infectious bronchitis virus in cultured cells. J. Virol. 2009;83:8744-8758.

    Not in our library10.1128/jvi.00613-09

  157. 157.

    Zhang S., Cao Y., Yang Q. Transferrin receptor 1 levels at the cell surface influence the susceptibility of newborn piglets to PEDV infection. PLoS Pathog. 2020;16:e1008682.

    Not in our library10.1371/journal.ppat.1008682

  158. 158.

    Xia S., Yan L., Xu W., Agrawal A.S., Algaissi A., Tseng C.K., Wang Q., Du L., Tan W., Wilson I.A., et al. A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Sci. Adv. 2019;5:eaav4580.

    Not in our library10.1126/sciadv.aav4580

  159. 159.

    Li F. Receptor recognition mechanisms of coronaviruses: A decade of structural studies. J. Virol. 2015;89:1954-1964.

    Not in our library10.1128/jvi.02615-14

  160. 160.

    Hofmann H., Pyrc K., van der Hoek L., Geier M., Berkhout B., Pohlmann S. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl. Acad. Sci. USA. 2005;102:7988-7993.

    Not in our library10.1073/pnas.0409465102

  161. 161.

    Xiao X., Chakraborti S., Dimitrov A.S., Gramatikoff K., Dimitrov D.S. The SARS-CoV S glycoprotein: Expression and functional characterization. Biochem. Biophys. Res. Commun. 2003;312:1159-1164.

    Not in our library10.1016/j.bbrc.2003.11.054

  162. 162.

    Raj V.S., Mou H., Smits S.L., Dekkers D.H., Muller M.A., Dijkman R., Muth D., Demmers J.A., Zaki A., Fouchier R.A., et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495:251-254.

    Not in our library10.1038/nature12005

  163. 163.

    Mou H., Raj V.S., van Kuppeveld F.J., Rottier P.J., Haagmans B.L., Bosch B.J. The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies. J. Virol. 2013;87:9379-9383.

    Not in our library10.1128/jvi.01277-13

  164. 164.

    Godet M., Grosclaude J., Delmas B., Laude H. Major receptor-binding and neutralization determinants are located within the same domain of the transmissible gastroenteritis virus (coronavirus) spike protein. J. Virol. 1994;68:8008-8016.

    Not in our library10.1128/jvi.68.12.8008-8016.1994

  165. 165.

    Peng G., Sun D., Rajashankar K.R., Qian Z., Holmes K.V., Li F. Crystal structure of mouse coronavirus receptor-binding domain complexed with its murine receptor. Proc. Natl. Acad. Sci. USA. 2011;108:10696-10701.

    Not in our library10.1073/pnas.1104306108

  166. 166.

    Wong A.H.M., Tomlinson A.C.A., Zhou D., Satkunarajah M., Chen K., Sharon C., Desforges M., Talbot P.J., Rini J.M. Receptor-binding loops in alphacoronavirus adaptation and evolution. Nat. Commun. 2017;8:1735.

    Not in our library10.1038/s41467-017-01706-x

  167. 167.

    Li W., Moore M.J., Vasilieva N., Sui J., Wong S.K., Berne M.A., Somasundaran M., Sullivan J.L., Luzuriaga K., Greenough T.C., et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450-454.

    Not in our library10.1038/nature02145

  168. 168.

    Delmas B., Gelfi J., L’Haridon R., Vogel L.K., Sjostrom H., Noren O., Laude H. Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV. Nature. 1992;357:417-420.

    Not in our library10.1038/357417a0

  169. 169.

    Kubo H., Yamada Y.K., Taguchi F. Localization of neutralizing epitopes and the receptor-binding site within the amino-terminal 330 amino acids of the murine coronavirus spike protein. J. Virol. 1994;68:5403-5410.

    Not in our library10.1128/jvi.68.9.5403-5410.1994

  170. 170.

    Krempl C., Schultze B., Laude H., Herrler G. Point mutations in the S protein connect the sialic acid binding activity with the enteropathogenicity of transmissible gastroenteritis coronavirus. J. Virol. 1997;71:3285-3287.

    Not in our library10.1128/jvi.71.4.3285-3287.1997

  171. 171.
    Crystal Structure of Bovine Coronavirus Spike Protein Lectin Domain · 2012
    No notice
  172. 172.

    Deng F., Ye G., Liu Q., Navid M.T., Zhong X., Li Y., Wan C., Xiao S., He Q., Fu Z.F., et al. Identification and Comparison of Receptor Binding Characteristics of the Spike Protein of Two Porcine Epidemic Diarrhea Virus Strains. Viruses. 2016;8:55.

    Not in our library10.3390/v8030055

  173. 173.

    Yang L., Xu J., Guo L., Guo T., Zhang L., Feng L., Chen H., Wang Y. Porcine Epidemic Diarrhea Virus-Induced Epidermal Growth Factor Receptor Activation Impairs the Antiviral Activity of Type I Interferon. J. Virol. 2018;92:e02095-17.

    Not in our library10.1128/jvi.02095-17

  174. 174.

    Li S., Zhu Z., Yang F., Cao W., Yang J., Ma C., Zhao Z., Tian H., Liu X., Ma J., et al. Porcine Epidemic Diarrhea Virus Membrane Protein Interacted with IRF7 to Inhibit Type I IFN Production during Viral Infection. J. Immunol. 2021;206:2909-2923.

    Not in our library10.4049/jimmunol.2001186

  175. 175.

    Dong S., Wang R., Yu R., Chen B., Si F., Xie C., Li Z. Identification of cellular proteins interacting with PEDV M protein through APEX2 labeling. J. Proteom. 2021;240:104191.

    Not in our library10.1016/j.jprot.2021.104191

  176. 176.

    Su M., Shi D., Xing X., Qi S., Yang D., Zhang J., Han Y., Zhu Q., Sun H., Wang X., et al. Coronavirus Porcine Epidemic Diarrhea Virus Nucleocapsid Protein Interacts with p53 To Induce Cell Cycle Arrest in S-Phase and Promotes Viral Replication. J. Virol. 2021;95:e0018721.

    Not in our library10.1128/jvi.00187-21

  177. 177.

    He Y., Smith R. Nuclear functions of heterogeneous nuclear ribonucleoproteins A/B. Cell Mol. Life Sci. 2009;66:1239-1256.

    Not in our library10.1007/s00018-008-8532-1

  178. 178.

    Li Z., Zeng W., Ye S., Lv J., Nie A., Zhang B., Sun Y., Han H., He Q. Cellular hnRNP A1 Interacts with Nucleocapsid Protein of Porcine Epidemic Diarrhea Virus and Impairs Viral Replication. Viruses. 2018;10:127.

    Not in our library10.3390/v10030127

  179. 179.

    Shan Y., Liu Z.Q., Li G.W., Chen C., Luo H., Liu Y.J., Zhuo X.H., Shi X.F., Fang W.H., Li X.L. Nucleocapsid protein from porcine epidemic diarrhea virus isolates can antagonize interferon-lambda production by blocking the nuclear factor-kappaB nuclear translocation. J. Zhejiang Univ. Sci. B. 2018;19:570-580.

    Not in our library10.1631/jzus.b1700283

  180. 180.

    Xu J., Mao J., Han X., Shi F., Gao Q., Wang T., Zhang Z., Shan Y., Fang W., Li X. Porcine Epidemic Diarrhea Virus Inhibits HDAC1 Expression To Facilitate Its Replication via Binding of Its Nucleocapsid Protein to Host Transcription Factor Sp1. J. Virol. 2021;95:e0085321.

    Not in our library10.1128/jvi.00853-21

  181. 181.

    Licciardi P.V., Karagiannis T.C. Regulation of immune responses by histone deacetylase inhibitors. ISRN Hematol. 2012;2012:690901.

    Not in our library10.5402/2012/690901

  182. 182.

    Zou D., Xu J., Duan X., Xu X., Li P., Cheng L., Zheng L., Li X., Zhang Y., Wang X., et al. Porcine epidemic diarrhea virus ORF3 protein causes endoplasmic reticulum stress to facilitate autophagy. Vet. Microbiol. 2019;235:209-219.

    Not in our library10.1016/j.vetmic.2019.07.005

  183. 183.

    Kaewborisuth C., He Q., Jongkaewwattana A. The Accessory Protein ORF3 Contributes to Porcine Epidemic Diarrhea Virus Replication by Direct Binding to the Spike Protein. Viruses. 2018;10:399.

    Not in our library10.3390/v10080399

  184. 184.

    Wu Z., Cheng L., Xu J., Li P., Li X., Zou D., Zhang Y., Wang X., Wu X., Shen Y., et al. The accessory protein ORF3 of porcine epidemic diarrhea virus inhibits cellular interleukin-6 and interleukin-8 productions by blocking the nuclear factor-kappaB p65 activation. Vet. Microbiol. 2020;251:108892.

    Not in our library10.1016/j.vetmic.2020.108892

  185. 185.

    Kaewborisuth C., Koonpaew S., Srisutthisamphan K., Viriyakitkosol R., Jaru-Ampornpan P., Jongkaewwattana A. PEDV ORF3 Independently Regulates IkappaB Kinase beta-Mediated NF-kappaB and IFN-beta Promoter Activities. Pathogens. 2020;9:376.

    Not in our library10.3390/pathogens9050376

  186. 186.

    Hofmann M.A., Senanayake S.D., Brian D.A. A translation-attenuating intraleader open reading frame is selected on coronavirus mRNAs during persistent infection. Proc. Natl. Acad. Sci. USA. 1993;90:11733-11737.

    Not in our library10.1073/pnas.90.24.11733

  187. 187.

    Zhang Q., Ke H., Blikslager A., Fujita T., Yoo D. Type III Interferon Restriction by Porcine Epidemic Diarrhea Virus and the Role of Viral Protein nsp1 in IRF1 Signaling. J. Virol. 2018;92:e01677-17.

    Not in our library10.1128/jvi.01677-17

  188. 188.

    Zhang Q., Ma J., Yoo D. Inhibition of NF-kappaB activity by the porcine epidemic diarrhea virus nonstructural protein 1 for innate immune evasion. Virology. 2017;510:111-126.

    Not in our library10.1016/j.virol.2017.07.009

  189. 189.

    Li M., Wu Y., Chen J., Shi H., Ji Z., Zhang X., Shi D., Liu J., Tian J., Wang X., et al. Innate Immune Evasion of Porcine Epidemic Diarrhea Virus through Degradation of the FBXW7 Protein via the Ubiquitin-Proteasome Pathway. J. Virol. 2022;96:e0088921.

    Not in our library10.1128/jvi.00889-21

  190. 190.

    Yu L., Dong J., Wang Y., Zhang P., Liu Y., Zhang L., Liang P., Wang L., Song C. Porcine epidemic diarrhea virus nsp4 induces pro-inflammatory cytokine and chemokine expression inhibiting viral replication in vitro. Arch. Virol. 2019;164:1147-1157.

    Not in our library10.1007/s00705-019-04176-2

  191. 191.

    Wang D., Fang L., Wei D., Zhang H., Luo R., Chen H., Li K., Xiao S. Hepatitis A virus 3C protease cleaves NEMO to impair induction of beta interferon. J. Virol. 2014;88:10252-10258.

    Not in our library10.1128/jvi.00869-14

  192. 192.

    Wang D., Fang L., Li K., Zhong H., Fan J., Ouyang C., Zhang H., Duan E., Luo R., Zhang Z., et al. Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling. J. Virol. 2012;86:9311-9322.

    Not in our library10.1128/jvi.00722-12

  193. 193.

    Huang C., Zhang Q., Guo X.K., Yu Z.B., Xu A.T., Tang J., Feng W.H. Porcine reproductive and respiratory syndrome virus nonstructural protein 4 antagonizes beta interferon expression by targeting the NF-kappaB essential modulator. J. Virol. 2014;88:10934-10945.

    Not in our library10.1128/jvi.01396-14

  194. 194.

    Wang D., Fang L., Shi Y., Zhang H., Gao L., Peng G., Chen H., Li K., Xiao S. Porcine Epidemic Diarrhea Virus 3C-Like Protease Regulates Its Interferon Antagonism by Cleaving NEMO. J. Virol. 2016;90:2090-2101.

    Not in our library10.1128/jvi.02514-15

  195. 195.

    Lin H., Li B., Liu M., Zhou H., He K., Fan H. Nonstructural protein 6 of porcine epidemic diarrhea virus induces autophagy to promote viral replication via the PI3K/Akt/mTOR axis. Vet. Microbiol. 2020;244:108684.

    Not in our library10.1016/j.vetmic.2020.108684

  196. 196.

    Sutton G., Fry E., Carter L., Sainsbury S., Walter T., Nettleship J., Berrow N., Owens R., Gilbert R., Davidson A., et al. The nsp9 replicase protein of SARS-coronavirus, structure and functional insights. Structure. 2004;12:341-353.

    Not in our library10.1016/j.str.2004.01.016

  197. 197.

    Guo L., Luo X., Li R., Xu Y., Zhang J., Ge J., Bu Z., Feng L., Wang Y. Porcine Epidemic Diarrhea Virus Infection Inhibits Interferon Signaling by Targeted Degradation of STAT1. J. Virol. 2016;90:8281-8292.

    Not in our library10.1128/jvi.01091-16

  198. 198.

    Zhang J., Yuan S., Peng Q., Ding Z., Hao W., Peng G., Xiao S., Fang L. Porcine Epidemic Diarrhea Virus nsp7 Inhibits Interferon-Induced JAK-STAT Signaling through Sequestering the Interaction between KPNA1 and STAT1. J. Virol. 2022;96:e0040022.

    Not in our library10.1128/jvi.00400-22

  199. 199.

    Ren J., Ding Z., Fang P., Xiao S., Fang L. ATPase and helicase activities of porcine epidemic diarrhea virus nsp13. Vet. Microbiol. 2021;257:109074.

    Not in our library10.1016/j.vetmic.2021.109074

  200. 200.

    Lu Y., Cai H., Lu M., Ma Y., Li A., Gao Y., Zhou J., Gu H., Li J., Gu J. Porcine Epidemic Diarrhea Virus Deficient in RNA Cap Guanine-N-7 Methylation Is Attenuated and Induces Higher Type I and III Interferon Responses. J. Virol. 2020;94:e00447-20.

    Not in our library10.1128/jvi.00447-20

  201. 201.

    Wu Y., Zhang H., Shi Z., Chen J., Li M., Shi H., Shi D., Guo L., Feng L. Porcine Epidemic Diarrhea Virus nsp15 Antagonizes Interferon Signaling by RNA Degradation of TBK1 and IRF3. Viruses. 2020;12:599.

    Not in our library10.3390/v12060599

  202. 202.

    Shi P., Su Y., Li R., Liang Z., Dong S., Huang J. PEDV nsp16 negatively regulates innate immunity to promote viral proliferation. Virus Res. 2019;265:57-66.

    Not in our library10.1016/j.virusres.2019.03.005

  203. 203.

    Li B.X., Ge J.W., Li Y.J. Porcine aminopeptidase N is a functional receptor for the PEDV coronavirus. Virology. 2007;365:166-172.

    Not in our library10.1016/j.virol.2007.03.031

  204. 204.

    Mina-Osorio P. The moonlighting enzyme CD13: Old and new functions to target. Trends Mol. Med. 2008;14:361-371.

    Not in our library10.1016/j.molmed.2008.06.003

  205. 205.

    Luo X., Guo L., Zhang J., Xu Y., Gu W., Feng L., Wang Y. Tight Junction Protein Occludin Is a Porcine Epidemic Diarrhea Virus Entry Factor. J. Virol. 2017;91:e00202-17.

    Not in our library10.1128/jvi.00202-17

  206. 206.

    Sawada N. Tight junction-related human diseases. Pathol. Int. 2013;63:1-12.

    Not in our library10.1111/pin.12021

  207. 207.

    Yun J.P., Chew E.C., Liew C.T., Chan J.Y., Jin M.L., Ding M.X., Fai Y.H., Li H.K., Liang X.M., Wu Q.L. Nucleophosmin/B23 is a proliferate shuttle protein associated with nuclear matrix. J. Cell Biochem. 2003;90:1140-1148.

    Not in our library10.1002/jcb.10706

  208. 208.

    Park J.Y., Ryu J., Park J.E., Hong E.J., Shin H.J. Heat shock protein 70 could enhance porcine epidemic diarrhoea virus replication by interacting with membrane proteins. Vet. Res. 2021;52:138.

    Not in our library10.1186/s13567-021-01006-9

  209. 209.
    EGF receptor trafficking: consequences for signaling and cancer · 2014
    No notice
  210. 210.

    Kong N., Shan T., Wang H., Jiao Y., Zuo Y., Li L., Tong W., Yu L., Jiang Y., Zhou Y., et al. BST2 suppresses porcine epidemic diarrhea virus replication by targeting and degrading virus nucleocapsid protein with selective autophagy. Autophagy. 2020;16:1737-1752.

    Not in our library10.1080/15548627.2019.1707487

  211. 211.

    Kupzig S., Korolchuk V., Rollason R., Sugden A., Wilde A., Banting G. Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic. 2003;4:694-709.

    Not in our library10.1034/j.1600-0854.2003.00129.x

  212. 212.

    Schmidt O., Teis D. The ESCRT machinery. Curr. Biol. 2012;22:R116-R120.

    Not in our library10.1016/j.cub.2012.01.028

  213. 213.

    Kaewborisuth C., Yingchutrakul Y., Roytrakul S., Jongkaewwattana A. Porcine Epidemic Diarrhea Virus (PEDV) ORF3 Interactome Reveals Inhibition of Virus Replication by Cellular VPS36 Protein. Viruses. 2019;11:382.

    Not in our library10.3390/v11040382

  214. 214.

    Zhao J., Chen J., Li M., Chen M., Sun C. Multifaceted Functions of CH25H and 25HC to Modulate the Lipid Metabolism, Immune Responses, and Broadly Antiviral Activities. Viruses. 2020;12:727.

    Not in our library10.3390/v12070727

  215. 215.

    Zhang Y., Song Z., Wang M., Lan M., Zhang K., Jiang P., Li Y., Bai J., Wang X. Cholesterol 25-hydroxylase negatively regulates porcine intestinal coronavirus replication by the production of 25-hydroxycholesterol. Vet. Microbiol. 2019;231:129-138.

    Not in our library10.1016/j.vetmic.2019.03.004

  216. 216.

    Sun L., Chen H., Ming X., Bo Z., Shin H.J., Jung Y.S., Qian Y. Porcine Epidemic Diarrhea Virus Infection Induces Caspase-8-Mediated G3BP1 Cleavage and Subverts Stress Granules To Promote Viral Replication. J. Virol. 2021;95:e02344-20.

    Not in our library10.1128/jvi.02344-20

  217. 217.

    Pandey K., Zhong S., Diel D.G., Hou Y., Wang Q., Nelson E., Wang X. GTPase-activating protein-binding protein 1 (G3BP1) plays an antiviral role against porcine epidemic diarrhea virus. Vet. Microbiol. 2019;236:108392.

    Not in our library10.1016/j.vetmic.2019.108392

  218. 218.

    Ramezani-Rad P., Leung C.R., Apgar J.R., Rickert R.C. E3 Ubiquitin Ligase Fbw7 Regulates the Survival of Mature B Cells. J. Immunol. 2020;204:1535-1542.

    Not in our library10.4049/jimmunol.1901156

  219. 219.

    Wang Y., Robertson J.D., Walcheck B. Different signaling pathways stimulate a disintegrin and metalloprotease-17 (ADAM17) in neutrophils during apoptosis and activation. J. Biol. Chem. 2011;286:38980-38988.

    Not in our library10.1074/jbc.m111.277087

  220. 220.

    Masutani M., Sonenberg N., Yokoyama S., Imataka H. Reconstitution reveals the functional core of mammalian eIF3. EMBO J. 2007;26:3373-3383.

    Not in our library10.1038/sj.emboj.7601765

  221. 221.

    Wang R., Yu R., Chen B., Si F., Wang J., Xie C., Men C., Dong S., Li Z. Identification of host cell proteins that interact with the M protein of porcine epidemic diarrhea virus. Vet. Microbiol. 2020;246:108729.

    Not in our library10.1016/j.vetmic.2020.108729

  222. 222.

    Kumar G.R., Shum L., Glaunsinger B.A. Importin alpha-mediated nuclear import of cytoplasmic poly(A) binding protein occurs as a direct consequence of cytoplasmic mRNA depletion. Mol. Cell Biol. 2011;31:3113-3125.

    Not in our library10.1128/mcb.05402-11

  223. 223.

    Aruffo A., Stamenkovic I., Melnick M., Underhill C.B., Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990;61:1303-1313.

    Not in our library10.1016/0092-8674(90)90694-a

  224. 224.

    Li Y., Li J., Wang X., Wu Q., Yang Q. Role of intestinal extracellular matrix-related signaling in porcine epidemic diarrhea virus infection. Virulence. 2021;12:2352-2365.

    Not in our library10.1080/21505594.2021.1972202

  225. 225.

    Garbers C., Scheller J. Interleukin-6 and interleukin-11: Same same but different. Biol. Chem. 2013;394:1145-1161.

    Not in our library10.1515/hsz-2013-0166

  226. 226.

    Yang L., Wang R., Gao Y., Xu X., Fu K., Wang S., Li Y., Peng R. The protective role of interleukin-11 against neutron radiation injury in mouse intestines via MEK/ERK and PI3K/Akt dependent pathways. Dig. Dis. Sci. 2014;59:1406-1414.

    Not in our library10.1007/s10620-013-3015-0

  227. 227.

    Uemura T., Nakayama T., Kusaba T., Yakata Y., Yamazumi K., Matsuu-Matsuyama M., Shichijo K., Sekine I. The protective effect of interleukin-11 on the cell death induced by X-ray irradiation in cultured intestinal epithelial cell. J. Radiat. Res. 2007;48:171-177.

    Not in our library10.1269/jrr.06047

  228. 228.

    Agthe M., Garbers Y., Putoczki T., Garbers C. Interleukin-11 classic but not trans-signaling is essential for fertility in mice. Placenta. 2017;57:13-16.

    Not in our library10.1016/j.placenta.2017.05.015

  229. 229.

    Li Y., Wu Q., Jin Y., Yang Q. Antiviral activity of interleukin-11 as a response to porcine epidemic diarrhea virus infection. Vet. Res. 2019;50:111.

    Not in our library10.1186/s13567-019-0729-9

  230. 230.

    Zenewicz L.A., Yancopoulos G.D., Valenzuela D.M., Murphy A.J., Stevens S., Flavell R.A. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29:947-957.

    Not in our library10.1016/j.immuni.2008.11.003

  231. 231.

    Basu R., O’Quinn D.B., Silberger D.J., Schoeb T.R., Fouser L., Ouyang W., Hatton R.D., Weaver C.T. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity. 2012;37:1061-1075.

    Not in our library10.1016/j.immuni.2012.08.024

  232. 232.

    Ouyang W., Rutz S., Crellin N.K., Valdez P.A., Hymowitz S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 2011;29:71-109.

    Not in our library10.1146/annurev-immunol-031210-101312

  233. 233.

    Yamashita M.S.A., Melo E.O. Mucin 2 (MUC2) promoter characterization: An overview. Cell Tissue Res. 2018;374:455-463.

    Not in our library10.1007/s00441-018-2916-9

  234. 234.

    Xiao Y., Zhou Y., Sun S., Wang H., Wu S., Bao W. Effect of Promoter Methylation on the Expression of Porcine MUC2 Gene and Resistance to PEDV Infection. Front. Vet. Sci. 2021;8:646408.

    Not in our library10.3389/fvets.2021.646408

  235. 235.

    Yeager C.L., Ashmun R.A., Williams R.K., Cardellichio C.B., Shapiro L.H., Look A.T., Holmes K.V. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature. 1992;357:420-422.

    Not in our library10.1038/357420a0

  236. 236.

    Kamau A.N., Park J.E., Park E.S., Yu J.E., Rho J., Shin H.J. Porcine amino peptidase N domain VII has critical role in binding and entry of porcine epidemic diarrhea virus. Virus Res. 2017;227:150-157.

    Not in our library10.1016/j.virusres.2016.10.004

  237. 237.

    Li W., Luo R., He Q., van Kuppeveld F.J.M., Rottier P.J.M., Bosch B.J. Aminopeptidase N is not required for porcine epidemic diarrhea virus cell entry. Virus Res. 2017;235:6-13.

    Not in our library10.1016/j.virusres.2017.03.018

  238. 238.

    Park J.E., Park E.S., Yu J.E., Rho J., Paudel S., Hyun B.H., Yang D.K., Shin H.J. Development of transgenic mouse model expressing porcine aminopeptidase N and its susceptibility to porcine epidemic diarrhea virus. Virus Res. 2015;197:108-115.

    Not in our library10.1016/j.virusres.2014.12.024

  239. 239.

    Shirato K., Maejima M., Islam M.T., Miyazaki A., Kawase M., Matsuyama S., Taguchi F. Porcine aminopeptidase N is not a cellular receptor of porcine epidemic diarrhea virus, but promotes its infectivity via aminopeptidase activity. J. Gen. Virol. 2016;97:2528-2539.

    Not in our library10.1099/jgv.0.000563

  240. 240.

    Schauer R. Sialic acids as regulators of molecular and cellular interactions. Curr. Opin. Struct. Biol. 2009;19:507-514.

    Not in our library10.1016/j.sbi.2009.06.003

  241. 241.

    Burzynska P., Sobala L.F., Mikolajczyk K., Jodlowska M., Jaskiewicz E. Sialic Acids as Receptors for Pathogens. Biomolecules. 2021;11:831.

    Not in our library10.3390/biom11060831

  242. 242.

    Wickramasinghe I.N., de Vries R.P., Grone A., de Haan C.A., Verheije M.H. Binding of avian coronavirus spike proteins to host factors reflects virus tropism and pathogenicity. J. Virol. 2011;85:8903-8912.

    Not in our library10.1128/jvi.05112-11

  243. 243.

    De Graaf M., Fouchier R.A. Role of receptor binding specificity in influenza A virus transmission and pathogenesis. EMBO J. 2014;33:823-841.

    Not in our library10.1002/embj.201387442

  244. 244.

    Li W., Hulswit R.J.G., Widjaja I., Raj V.S., McBride R., Peng W., Widagdo W., Tortorici M.A., van Dieren B., Lang Y., et al. Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proc. Natl. Acad. Sci. USA. 2017;114:E8508-E8517.

    Not in our library10.1073/pnas.1712592114

  245. 245.

    Schultze B., Enjuanes L., Cavanagh D., Herrler G. N-acetylneuraminic acid plays a critical role for the haemagglutinating activity of avian infectious bronchitis virus and porcine transmissible gastroenteritis virus. Adv. Exp. Med. Biol. 1993;342:305-310.

    Not in our library10.1007/978-1-4615-2996-5_47

  246. 246.

    Furuse M., Izumi Y., Oda Y., Higashi T., Iwamoto N. Molecular organization of tricellular tight junctions. Tissue Barriers. 2014;2:e28960.

    Not in our library10.4161/tisb.28960

  247. 247.

    Torres-Flores J.M., Arias C.F. Tight Junctions Go Viral! Viruses. 2015;7:5145-5154.

    Not in our library10.3390/v7092865

  248. 248.

    Ploss A., Evans M.J., Gaysinskaya V.A., Panis M., You H., de Jong Y.P., Rice C.M. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature. 2009;457:882-886.

    Not in our library10.1038/nature07684

  249. 249.

    Coyne C.B., Shen L., Turner J.R., Bergelson J.M. Coxsackievirus entry across epithelial tight junctions requires occludin and the small GTPases Rab34 and Rab5. Cell Host Microbe. 2007;2:181-192.

    Not in our library10.1016/j.chom.2007.07.003

  250. 250.

    Zong Q.F., Huang Y.J., Wu L.S., Wu Z.C., Wu S.L., Bao W.B. Effects of porcine epidemic diarrhea virus infection on tight junction protein gene expression and morphology of the intestinal mucosa in pigs. Pol J. Vet. Sci. 2019;22:345-353.

    Not in our library10.24425/pjvs.2019.129226

  251. 251.

    Fankhauser C., Izaurralde E., Adachi Y., Wingfield P., Laemmli U.K. Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: Dissociation by the Rev response element. Mol. Cell Biol. 1991;11:2567-2575.

    Not in our library10.1128/mcb.11.5.2567-2575.1991

  252. 252.

    Tsuda Y., Mori Y., Abe T., Yamashita T., Okamoto T., Ichimura T., Moriishi K., Matsuura Y. Nucleolar protein B23 interacts with Japanese encephalitis virus core protein and participates in viral replication. Microbiol. Immunol. 2006;50:225-234.

    Not in our library10.1111/j.1348-0421.2006.tb03789.x

  253. 253.

    Samad M.A., Okuwaki M., Haruki H., Nagata K. Physical and functional interaction between a nucleolar protein nucleophosmin/B23 and adenovirus basic core proteins. FEBS Lett. 2007;581:3283-3288.

    Not in our library10.1016/j.febslet.2007.06.024

  254. 254.

    Lymberopoulos M.H., Bourget A., Ben Abdeljelil N., Pearson A. Involvement of the UL24 protein in herpes simplex virus 1-induced dispersal of B23 and in nuclear egress. Virology. 2011;412:341-348.

    Not in our library10.1016/j.virol.2011.01.016

  255. 255.

    Liu C.D., Chen Y.L., Min Y.L., Zhao B., Cheng C.P., Kang M.S., Chiu S.J., Kieff E., Peng C.W. The nuclear chaperone nucleophosmin escorts an Epstein-Barr Virus nuclear antigen to establish transcriptional cascades for latent infection in human B cells. PLoS Pathog. 2012;8:e1003084.

    Not in our library10.1371/journal.ppat.1003084

  256. 256.

    Passos-Castilho A.M., Marchand C., Archambault D. B23/nucleophosmin interacts with bovine immunodeficiency virus Rev protein and facilitates viral replication. Virology. 2018;515:158-164.

    Not in our library10.1016/j.virol.2017.12.021

  257. 257.

    Zhou J., Li J., Li H., Zhang Y., Dong W., Jin Y., Yan Y., Gu J., Zhou J. The serine-48 residue of nucleolar phosphoprotein nucleophosmin-1 plays critical role in subcellular localization and interaction with porcine circovirus type 3 capsid protein. Vet. Res. 2021;52:4.

    Not in our library10.1186/s13567-020-00876-9

  258. 258.
    Nucleolar Phosphoprotein NPM1 Interacts With Porcine Circovirus Type 3 Cap Protein and Facilitates Viral Replication · 2021
    Not checked
  259. 259.
    Nucleolar protein NPM1 is essential for circovirus replication by binding to viral capsid · 2020
    Not checked
  260. 260.

    Abraham R., Singh S., Nair S.R., Hulyalkar N.V., Surendran A., Jaleel A., Sreekumar E. Nucleophosmin (NPM1)/B23 in the Proteome of Human Astrocytic Cells Restricts Chikungunya Virus Replication. J. Proteome Res. 2017;16:4144-4155.

    Not in our library10.1021/acs.jproteome.7b00513

  261. 261.

    Hartl F.U., Hayer-Hartl M. Molecular chaperones in the cytosol: From nascent chain to folded protein. Science. 2002;295:1852-1858.

    Not in our library10.1126/science.1068408

  262. 262.

    Maggioni C., Braakman I. Synthesis and quality control of viral membrane proteins. Curr Top. Microbiol. Immunol. 2005;285:175-198.

    Not in our library10.1007/3-540-26764-6_6

  263. 263.

    Nagy P.D., Wang R.Y., Pogany J., Hafren A., Makinen K. Emerging picture of host chaperone and cyclophilin roles in RNA virus replication. Virology. 2011;411:374-382.

    Not in our library10.1016/j.virol.2010.12.061

  264. 264.

    Hirayama E., Atagi H., Hiraki A., Kim J. Heat shock protein 70 is related to thermal inhibition of nuclear export of the influenza virus ribonucleoprotein complex. J. Virol. 2004;78:1263-1270.

    Not in our library10.1128/jvi.78.3.1263-1270.2004

  265. 265.

    De Marco A., Santoro M.G. Antiviral effect of short hyperthermic treatment at specific stages of vesicular stomatitis virus replication cycle. J. Gen. Virol. 1993;74:1685-1690.

    Not in our library10.1099/0022-1317-74-8-1685

  266. 266.

    Lupberger J., Zeisel M.B., Xiao F., Thumann C., Fofana I., Zona L., Davis C., Mee C.J., Turek M., Gorke S., et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 2011;17:589-595.

    Not in our library10.1038/nm.2341

  267. 267.

    Diao J., Pantua H., Ngu H., Komuves L., Diehl L., Schaefer G., Kapadia S.B. Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry. J. Virol. 2012;86:10935-10949.

    Not in our library10.1128/jvi.00750-12

  268. 268.

    Hu W., Zhang S., Shen Y., Yang Q. Epidermal growth factor receptor is a co-factor for transmissible gastroenteritis virus entry. Virology. 2018;521:33-43.

    Not in our library10.1016/j.virol.2018.05.009

  269. 269.
    The Epidermal Growth Factor Receptor (EGFR) Promotes Uptake of Influenza A Viruses (IAV) into Host Cells · 2010
    No notice
  270. 270.

    Klann K., Bojkova D., Tascher G., Ciesek S., Munch C., Cinatl J. Growth Factor Receptor Signaling Inhibition Prevents SARS-CoV-2 Replication. Mol. Cell. 2020;80:164-174.e164.

    Not in our library10.1016/j.molcel.2020.08.006

  271. 271.

    Wang S.M., Huang K.J., Wang C.T. BST2/CD317 counteracts human coronavirus 229E productive infection by tethering virions at the cell surface. Virology. 2014;449:287-296.

    Not in our library10.1016/j.virol.2013.11.030

  272. 272.

    Pan X.B., Qu X.W., Jiang D., Zhao X.L., Han J.C., Wei L. BST2/Tetherin inhibits hepatitis C virus production in human hepatoma cells. Antiviral. Res. 2013;98:54-60.

    Not in our library10.1016/j.antiviral.2013.01.009

  273. 273.

    Pan X.B., Han J.C., Cong X., Wei L. BST2/tetherin inhibits dengue virus release from human hepatoma cells. PLoS ONE. 2012;7:e51033.

    Not in our library10.1371/journal.pone.0051033

  274. 274.

    Li M., Wang P., Zheng Z., Hu K., Zhang M., Guan X., Fu M., Zhang D., Wang W., Xiao G., et al. Japanese encephalitis virus counteracts BST2 restriction via its envelope protein E. Virology. 2017;510:67-75.

    Not in our library10.1016/j.virol.2017.07.008

  275. 275.

    Le Tortorec A., Neil S.J. Antagonism to and intracellular sequestration of human tetherin by the human immunodeficiency virus type 2 envelope glycoprotein. J. Virol. 2009;83:11966-11978.

    Not in our library10.1128/jvi.01515-09

  276. 276.

    Neil S.J., Zang T., Bieniasz P.D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008;451:425-430.

    Not in our library10.1038/nature06553

  277. 277.

    Jouvenet N., Neil S.J., Zhadina M., Zang T., Kratovac Z., Lee Y., McNatt M., Hatziioannou T., Bieniasz P.D. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J. Virol. 2009;83:1837-1844.

    Not in our library10.1128/jvi.02211-08

  278. 278.

    Sakuma T., Noda T., Urata S., Kawaoka Y., Yasuda J. Inhibition of Lassa and Marburg virus production by tetherin. J. Virol. 2009;83:2382-2385.

    Not in our library10.1128/jvi.01607-08

  279. 279.

    Blondeau C., Pelchen-Matthews A., Mlcochova P., Marsh M., Milne R.S., Towers G.J. Tetherin restricts herpes simplex virus 1 and is antagonized by glycoprotein M. J. Virol. 2013;87:13124-13133.

    Not in our library10.1128/jvi.02250-13

  280. 280.

    Viswanathan K., Smith M.S., Malouli D., Mansouri M., Nelson J.A., Fruh K. BST2/Tetherin enhances entry of human cytomegalovirus. PLoS Pathog. 2011;7:e1002332.

    Not in our library10.1371/journal.ppat.1002332

  281. 281.

    Teo H., Perisic O., Gonzalez B., Williams R.L. ESCRT-II, an endosome-associated complex required for protein sorting: Crystal structure and interactions with ESCRT-III and membranes. Dev. Cell. 2004;7:559-569.

    Not in our library10.1016/j.devcel.2004.09.003

  282. 282.

    Daniloski Z., Jordan T.X., Wessels H.H., Hoagland D.A., Kasela S., Legut M., Maniatis S., Mimitou E.P., Lu L., Geller E., et al. Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells. Cell. 2021;184:92-105.e116.

    Not in our library10.1016/j.cell.2020.10.030

  283. 283.

    Wang R., Simoneau C.R., Kulsuptrakul J., Bouhaddou M., Travisano K.A., Hayashi J.M., Carlson-Stevermer J., Zengel J.R., Richards C.M., Fozouni P., et al. Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses. Cell. 2021;184:106-119.e114.

    Not in our library10.1016/j.cell.2020.12.004

  284. 284.

    Wilkins C., Gale M. Sterol-izing innate immunity. Immunity. 2013;38:3-5.

    Not in our library10.1016/j.immuni.2013.01.002

  285. 285.

    Liu S.Y., Aliyari R., Chikere K., Li G., Marsden M.D., Smith J.K., Pernet O., Guo H., Nusbaum R., Zack J.A., et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity. 2013;38:92-105.

    Not in our library10.1016/j.immuni.2012.11.005

  286. 286.

    Yuan Y., Wang Z., Tian B., Zhou M., Fu Z.F., Zhao L. Cholesterol 25-hydroxylase suppresses rabies virus infection by inhibiting viral entry. Arch. Virol. 2019;164:2963-2974.

    Not in our library10.1007/s00705-019-04415-6

  287. 287.

    Shrivastava-Ranjan P., Bergeron E., Chakrabarti A.K., Albarino C.G., Flint M., Nichol S.T., Spiropoulou C.F. 25-Hydroxycholesterol Inhibition of Lassa Virus Infection through Aberrant GP1 Glycosylation. mBio. 2016;7:e01808-16.

    Not in our library10.1128/mbio.01808-16

  288. 288.

    Magoro T., Dandekar A., Jennelle L.T., Bajaj R., Lipkowitz G., Angelucci A.R., Bessong P.O., Hahn Y.S. IL-1beta/TNF-alpha/IL-6 inflammatory cytokines promote STAT1-dependent induction of CH25H in Zika virus-infected human macrophages. J. Biol. Chem. 2019;294:14591-14602.

    Not in our library10.1074/jbc.ra119.007555

  289. 289.

    Roulin P.S., Lotzerich M., Torta F., Tanner L.B., van Kuppeveld F.J., Wenk M.R., Greber U.F. Rhinovirus uses a phosphatidylinositol 4-phosphate/cholesterol counter-current for the formation of replication compartments at the ER-Golgi interface. Cell Host Microbe. 2014;16:677-690.

    Not in our library10.1016/j.chom.2014.10.003

  290. 290.

    Wang J., Zeng L., Zhang L., Guo Z.Z., Lu S.F., Ming S.L., Li G.L., Wan B., Tian K.G., Yang G.Y., et al. Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication. J. Gen. Virol. 2017;98:1467-1476.

    Not in our library10.1099/jgv.0.000797

  291. 291.

    Ke W., Fang L., Jing H., Tao R., Wang T., Li Y., Long S., Wang D., Xiao S. Cholesterol 25-Hydroxylase Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication through Enzyme Activity-Dependent and -Independent Mechanisms. J. Virol. 2017;91:e00827-17.

    Not in our library10.1128/jvi.00827-17

  292. 292.

    Dong H., Zhou L., Ge X., Guo X., Han J., Yang H. Antiviral effect of 25-hydroxycholesterol against porcine reproductive and respiratory syndrome virus in vitro. Antivir. Ther. 2018;23:395-404.

    Not in our library10.3851/imp3232

  293. 293.

    Ge Y., Jin J., Li J., Ye M., Jin X. The roles of G3BP1 in human diseases (review). Gene. 2022;821:146294.

    Not in our library10.1016/j.gene.2022.146294

  294. 294.

    Tourriere H., Chebli K., Zekri L., Courselaud B., Blanchard J.M., Bertrand E., Tazi J. The RasGAP-associated endoribonuclease G3BP assembles stress granules. J. Cell Biol. 2003;160:823-831.

    Not in our library10.1083/jcb.200212128

  295. 295.

    McCormick C., Khaperskyy D.A. Translation inhibition and stress granules in the antiviral immune response. Nat. Rev. Immunol. 2017;17:647-660.

    Not in our library10.1038/nri.2017.63

  296. 296.

    Yang W., Ru Y., Ren J., Bai J., Wei J., Fu S., Liu X., Li D., Zheng H. G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral response. Cell Death Dis. 2019;10:946.

    Not in our library10.1038/s41419-019-2178-9

  297. 297.
    Seneca Valley Virus 3C Protease Inhibits Stress Granule Formation by Disrupting eIF4GI-G3BP1 Interaction · 2020
    Not checked
  298. 298.

    Humoud M.N., Doyle N., Royall E., Willcocks M.M., Sorgeloos F., van Kuppeveld F., Roberts L.O., Goodfellow I.G., Langereis M.A., Locker N. Feline Calicivirus Infection Disrupts Assembly of Cytoplasmic Stress Granules and Induces G3BP1 Cleavage. J. Virol. 2016;90:6489-6501.

    Not in our library10.1128/jvi.00647-16

  299. 299.

    Ng C.S., Jogi M., Yoo J.S., Onomoto K., Koike S., Iwasaki T., Yoneyama M., Kato H., Fujita T. Encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune responses. J. Virol. 2013;87:9511-9522.

    Not in our library10.1128/jvi.03248-12

  300. 300.

    Visser L.J., Medina G.N., Rabouw H.H., de Groot R.J., Langereis M.A., de Los Santos T., van Kuppeveld F.J.M. Foot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule Formation. J. Virol. 2019;93:e00922-18.

    Not in our library10.1128/jvi.00922-18

  301. 301.

    Panas M.D., Varjak M., Lulla A., Eng K.E., Merits A., Karlsson Hedestam G.B., McInerney G.M. Sequestration of G3BP coupled with efficient translation inhibits stress granules in Semliki Forest virus infection. Mol. Biol. Cell. 2012;23:4701-4712.

    Not in our library10.1091/mbc.e12-08-0619

  302. 302.

    Yang X., Hu Z., Zhang Q., Fan S., Zhong Y., Guo D., Qin Y., Chen M. SG formation relies on eIF4GI-G3BP interaction which is targeted by picornavirus stress antagonists. Cell Discov. 2019;5:1.

    Not in our library10.1038/s41421-018-0068-4

  303. 303.

    White J.P., Cardenas A.M., Marissen W.E., Lloyd R.E. Inhibition of cytoplasmic mRNA stress granule formation by a viral proteinase. Cell Host Microbe. 2007;2:295-305.

    Not in our library10.1016/j.chom.2007.08.006

  304. 304.
    SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response · 2022
    Not checked
  305. 305.
    Influenza A Virus Host Shutoff Disables Antiviral Stress-Induced Translation Arrest · 2014
    No notice
  306. 306.

    Zhao D., Li J., Wang Y., Li X., Gao L., Cao H., Zheng S.J. Critical role for G3BP1 in infectious bursal disease virus (IBDV)-induced stress granule formation and viral replication. Vet. Microbiol. 2020;248:108806.

    Not in our library10.1016/j.vetmic.2020.108806

  307. 307.

    Choudhury P., Bussiere L.D., Miller C.L. Mammalian Orthoreovirus Factories Modulate Stress Granule Protein Localization by Interaction with G3BP1. J. Virol. 2017;91:e01298-17.

    Not in our library10.1128/jvi.01298-17

  308. 308.

    Scholte F.E., Tas A., Albulescu I.C., Zusinaite E., Merits A., Snijder E.J., van Hemert M.J. Stress granule components G3BP1 and G3BP2 play a proviral role early in Chikungunya virus replication. J. Virol. 2015;89:4457-4469.

    Not in our library10.1128/jvi.03612-14

  309. 309.

    Wang Z., Inuzuka H., Fukushima H., Wan L., Gao D., Shaik S., Sarkar F.H., Wei W. Emerging roles of the FBW7 tumour suppressor in stem cell differentiation. EMBO Rep. 2011;13:36-43.

    Not in our library10.1038/embor.2011.231

  310. 310.

    Chen J., Wu X., Chen S., Chen S., Xiang N., Chen Y., Guo D. Ubiquitin ligase Fbw7 restricts the replication of hepatitis C virus by targeting NS5B for ubiquitination and degradation. Biochem. Biophys. Res. Commun. 2016;470:697-703.

    Not in our library10.1016/j.bbrc.2016.01.076

  311. 311.
    ADAM17-dependent signaling is required for oncogenic human papillomavirus entry platform assembly · 2019
    Not checked
  312. 312.

    Arenaccio C., Chiozzini C., Columba-Cabezas S., Manfredi F., Affabris E., Baur A., Federico M. Exosomes from human immunodeficiency virus type 1 (HIV-1)-infected cells license quiescent CD4+ T lymphocytes to replicate HIV-1 through a Nef- and ADAM17-dependent mechanism. J. Virol. 2014;88:11529-11539.

    Not in our library10.1128/jvi.01712-14

  313. 313.

    Yuan F., Li D., Li C., Zhang Y., Song H., Li S., Deng H., Gao G.F., Zheng A. ADAM17 is an essential attachment factor for classical swine fever virus. PLoS Pathog. 2021;17:e1009393.

    Not in our library10.1371/journal.ppat.1009393

  314. 314.

    Heurich A., Hofmann-Winkler H., Gierer S., Liepold T., Jahn O., Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J. Virol. 2014;88:1293-1307.

    Not in our library10.1128/jvi.02202-13

  315. 315.

    Guo L., Niu J., Yu H., Gu W., Li R., Luo X., Huang M., Tian Z., Feng L., Wang Y. Modulation of CD163 expression by metalloprotease ADAM17 regulates porcine reproductive and respiratory syndrome virus entry. J. Virol. 2014;88:10448-10458.

    Not in our library10.1128/jvi.01117-14

  316. 316.

    Zhang J., Guo L., Yang L., Xu J., Zhang L., Feng L., Chen H., Wang Y. Metalloprotease ADAM17 regulates porcine epidemic diarrhea virus infection by modifying aminopeptidase N. Virology. 2018;517:24-29.

    Not in our library10.1016/j.virol.2018.02.001

  317. 317.

    Valente S.T., Gilmartin G.M., Mott C., Falkard B., Goff S.P. Inhibition of HIV-1 replication by eIF3f. Proc. Natl. Acad. Sci. USA. 2009;106:4071-4078.

    Not in our library10.1073/pnas.0900557106

  318. 318.

    Morais A., Terzian A.C., Duarte D.V., Bronzoni R.V., Madrid M.C., Gavioli A.F., Gil L.H., Oliveira A.G., Zanelli C.F., Valentini S.R., et al. The eukaryotic translation initiation factor 3 subunit L protein interacts with Flavivirus NS5 and may modulate yellow fever virus replication. Virol. J. 2013;10:205.

    Not in our library10.1186/1743-422x-10-205

  319. 319.

    Holcomb D., Alexaki A., Hernandez N., Hunt R., Laurie K., Kames J., Hamasaki-Katagiri N., Komar A.A., DiCuccio M., Kimchi-Sarfaty C. Gene variants of coagulation related proteins that interact with SARS-CoV-2. PLoS Comput. Biol. 2021;17:e1008805.

    Not in our library10.1371/journal.pcbi.1008805

  320. 320.

    Jiao Y., Kong N., Wang H., Sun D., Dong S., Chen X., Zheng H., Tong W., Yu H., Yu L., et al. PABPC4 Broadly Inhibits Coronavirus Replication by Degrading Nucleocapsid Protein through Selective Autophagy. Microbiol. Spectr. 2021;9:e0090821.

    Not in our library10.1128/spectrum.00908-21

  321. 321.

    Orian-Rousseau V., Sleeman J. CD44 is a multidomain signaling platform that integrates extracellular matrix cues with growth factor and cytokine signals. Adv. Cancer Res. 2014;123:231-254.

    Not in our library10.1016/b978-0-12-800092-2.00009-5

  322. 322.

    Ponta H., Sherman L., Herrlich P.A. CD44: From adhesion molecules to signalling regulators. Nat. Rev. Mol. Cell Biol. 2003;4:33-45.

    Not in our library10.1038/nrm1004

  323. 323.

    Heldin P., Basu K., Kozlova I., Porsch H. HAS2 and CD44 in breast tumorigenesis. Adv. Cancer Res. 2014;123:211-229.

    Not in our library10.1016/b978-0-12-800092-2.00008-3

  324. 324.

    Bouchard M.J., Racaniello V.R. CD44 is not required for poliovirus replication. J. Virol. 1997;71:2793-2798.

    Not in our library10.1128/jvi.71.4.2793-2798.1997

  325. 325.

    Goujon C., Rebendenne A., Roy P., Bonaventure B., Valadao A.C., Desmarets L., Rouille Y., Tauziet M., Arnaud-Arnould M., Giovannini D., et al. Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs. Res. Sq. 2021.

    Not in our library10.21203/rs.3.rs-555275/v1

  326. 326.

    Liu A., Pan Q., Wang S., Zhang Y., Li Y., Wang Y., Qi X., Gao L., Liu C., Zhang Y., et al. Identification of Chicken CD44 as a Novel B Lymphocyte Receptor for Infectious Bursal Disease Virus. J. Virol. 2022;96:e0011322.

    Not in our library10.1128/jvi.00113-22

  327. 327.

    Favors S.E., Curd L.M., Gregg R.K. Use of the anti-inflammatory cytokine interleukin-11 to reverse HIV-1gp120 repression of a natural killer cell line. Cell Immunol. 2012;276:1-5.

    Not in our library10.1016/j.cellimm.2012.02.011

  328. 328.

    Xue M., Zhao J., Ying L., Fu F., Li L., Ma Y., Shi H., Zhang J., Feng L., Liu P. IL-22 suppresses the infection of porcine enteric coronaviruses and rotavirus by activating STAT3 signal pathway. Antiviral. Res. 2017;142:68-75.

    Not in our library10.1016/j.antiviral.2017.03.006

  329. 329.
    Interleukin-22 Inhibits Respiratory Syncytial Virus Production by Blocking Virus-Mediated Subversion of Cellular Autophagy · 2020
    Not checked
  330. 330.

    Liu Y., Yu X., Zhao J., Zhang H., Zhai Q., Chen W. The role of MUC2 mucin in intestinal homeostasis and the impact of dietary components on MUC2 expression. Int. J. Biol. Macromol. 2020;164:884-891.

    Not in our library10.1016/j.ijbiomac.2020.07.191

  331. 331.

    McCauley H.A., Guasch G. Three cheers for the goblet cell: Maintaining homeostasis in mucosal epithelia. Trends Mol. Med. 2015;21:492-503.

    Not in our library10.1016/j.molmed.2015.06.003

  332. 332.
    Damage to intestinal barrier integrity in piglets caused by porcine reproductive and respiratory syndrome virus infection · 2021
    Not checked
  333. 333.

    Bartel D.P. MicroRNAs: Target recognition and regulatory functions. Cell. 2009;136:215-233.

    Not in our library10.1016/j.cell.2009.01.002

  334. 334.

    Zheng H., Xu L., Liu Y., Li C., Zhang L., Wang T., Zhao D., Xu X., Zhang Y. MicroRNA-221-5p Inhibits Porcine Epidemic Diarrhea Virus Replication by Targeting Genomic Viral RNA and Activating the NF-kappaB Pathway. Int. J. Mol. Sci. 2018;19:3381.

    Not in our library10.3390/ijms19113381

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