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Helicobacter pylori Virulence Factors Exploiting Gastric Colonization and its Pathogenicity

Shamshul Ansari, Yoshio Yamaoka

Toxins · 2019 · Review · CC BY

doi:10.3390/toxins11110677

Abstract

Helicobacter pylori colonizes the gastric epithelial cells of at least half of the world’s population, and it is the strongest risk factor for developing gastric complications like chronic gastritis, ulcer diseases, and gastric cancer. To successfully colonize and establish a persistent infection, the bacteria must overcome harsh gastric conditions. H. pylori has a well-developed mechanism by which it can survive in a very acidic niche. Despite bacterial factors, gastric environmental factors and host genetic constituents together play a co-operative role for gastric pathogenicity. The virulence factors include bacterial colonization factors BabA, SabA, OipA, and HopQ, and the virulence factors necessary for gastric pathogenicity include the effector proteins like CagA, VacA, HtrA, and the outer membrane vesicles. Bacterial factors are considered more important. Here, we summarize the recent information to better understand several bacterial virulence factors and their role in the pathogenic mechanism.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Background

Helicobacter pylori, one of the most common bacteria to colonize the gastric epithelium of about half of the world’s population, has been estimated to accompany humans for at least 100,000 years. Based on epidemiological data, the bacterium has been categorized as a class-I carcinogen, because it is the strongest known risk factor for severe gastric complication development. Geographic variation was found to influence infection prevalence between countries, and socio-economic status, urbanization level and poor sanitation during childhood has been linked to infection prevalence variation between countries. A recent meta-analysis found that the estimated overall global prevalence was 44.3%, with the prevalence as high as 89.7% in Nigeria and as low as 8.9% in Yemen.

Although the exact route of bacterial transmission is unknown, documented evidence supports oral–oral or fecal–oral transmission from person to person between family members, and it shows a greater chance of acquiring the infection in the early years of life. After its transition to the gastric lumen, H. pylori colonizes specific sites like the antrum and corpus. H. pylori has well-developed adaptation mechanisms to survive in the harsh gastric acid conditions and to establish a permanent infection (reviewed by Ansari and Yamaoka).

Once the permanent infection is established in the stomach, several gastro-duodenal complications like chronic gastritis, peptic ulcer diseases, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma may develop. However, the frequency of patients developing severe complications is very low; it has been estimated that less than 1, 10–300, and 100–1000 patients develop MALT lymphoma, gastric cancer, and peptic ulcer diseases, respectively, among every 10,000 patients infected with H. pylori. It has been found that approximately 70% of all gastric ulcers and up to 80% of all duodenal ulcers are caused by H. pylori infection, which is a significant factor causing non-iatrogenic peptic ulcer diseases. The risk of peptic ulcer development increases with previous history of H. pylori infection even after its successful eradication compared with non-infected individuals. However, investigations indicate that the recurrence of peptic ulcer diseases decreases with the successful eradication of H. pylori infection compared to non-cured patients. The results of a study on the relationship between ulcer disease recurrences and H. pylori eradication status found that the recurrence rate of gastric ulcers and peptic ulcers were 4% and 6%, respectively, in successfully cured patients compared to 59% and 67%, respectively, in non-cured patients. However, the development of gastric complications like peptic ulcer diseases and gastric cancer is a long-term process that may take several decades, and it is a multifactorial process influenced by gastric environmental, host genetic, and bacterial virulence factors.

2. Virulence Factors Associated with Escape to High Acidic Environment

After transit to the gastric lumen, the H. pylori encounters extremely harsh conditions of pH around 2.0. However, H. pylori possesses several factors like urease, bacterial shape and flagella mediating motility to interact with the harsh gastric environment (Table 1). The acidic conditions help the bacteria to express some genetic determinants that neutralize the acidic environment (reviewed by Ansari and Yamaoka).

2.1. Urease

A large amount of intracellular urease is produced by H. pylori, constituting around 10% of the total bacterial protein production. In addition to intracellular urease, H. pylori also contains extracellular urease on the bacterial surface due to the lysis of some bacteria in the stomach.

Urease-catalyzed urea hydrolysis (endogenous and exogenous) results in ammonia (NH3) and carbamate production, which is spontaneously decomposed to yield another ammonia (NH3) and carbonic acid (H2CO3). The carbonic acid is broken down to CO2 and water (H2O) molecules. Ammonia in its protonated form (NH4+) neutralizes stomach acidity and plays an important role in providing a favorable nearly neutral micro-environment around H. pylori. CO2 is converted to bicarbonate (HCO3−) and H+ in the periplasmic space by periplasmic α-carbonic anhydrase, maintaining the periplasmic pH close to 6.1 via an acid acclimation mechanism. In this way, NH3 and CO2 production provides the necessary environment for H. pylori’s gastric survival. However, continuous urease expression is required by bacteria for successful colonization even after its survival adaptation in the stomach.

In addition to its role in acid neutralization, several in vitro studies uncovered urease’s role and its catalytic products in pathogenicity establishment. Ammonia production disrupts the tight cell junctions, breaches the cellular integrity, and damages the gastric epithelium. CO2 protects the bacterium from the bactericidal activity of metabolic products like nitric oxide and intracellular killing by phagocytes. Urease was recently reported to possibly contribute to tumor growth and metastatic dissemination by inducing angiogenesis, or new blood vessel formation from pre-existing vasculature, and playing a key role in gastric cancer progression. Chronic H. pylori infection has been found to induce hypoxia-induced factor (HIF), which contributes to the development and progression of several cancers. A recent study showed that the H. pylori urease activated the PI3K-AKT-mTOR pathway in gastric cells. The activation of this pathway increases HIF-α expression. Moreover, H. pylori urease was found to drive the differentiation of endothelial cells by producing reactive oxygen species and activating the lipoxygenase pathway via pro-inflammatory properties, contributing to H. pylori infection progression to gastric carcinogenesis. Furthermore, H. pylori urease was shown to bind to major histocompatibility complex (MHC) class II molecules and induce cell apoptosis.

2.2. Bacterial Shape

A study of the bacterial shape’s role in movement showed that a mutation in the cell shape determinants causing the bacteria to adopt a straight rod morphology reduced the speed of bacterial movement by 7–21%. Moreover, the results of another study using a mouse infection model showed that the mutant curved H. pylori were outcompeted by wild type helical H. pylori. These studies suggest that the helical shape is important for the bacterium to penetrate into and move within the viscous mucous layer and for H. pylori’s efficient colonization.

The characteristic helical shape of bacteria which provides the bacterial motility also helps to cope with the harsh acidic conditions and adapt to different gastric environments. After transiting to the stomach, the bacteria move from acidic conditions to the mucus layer, which provides a protective layer, before finally moving to the gastric epithelium to establish colonization and infection. The helical bacterial shape facilitates the rapid corkscrew-like bacterial movement within the less acidic mucus layer, allowing the bacterium to escape the extremely low gastric pH. Moreover, another study highlights the importance of the bacterial helical shape and motility for penetrating the mucus layer and colonizing the gastric epithelium.

2.3. Flagella Mediating Motility

The flagellum is the locomotory organ that enables the bacterium to move in the ecological niche. H. pylori normally possesses two to six sheathed flagella about 3 μm long at one pole. Despite providing harsh conditions, the acid exposure in the gastric niche also activates some proteins that help to escape from the danger. It has been shown that acid exposure activates flagellin, the flagellar proteins leading to enhanced motility. In a study by Merrell et al., the larger percentage of acid-exposed bacteria displayed significantly higher speeds compared to non-acid-exposed bacteria.

The number of flagella plays a crucial role in the bacterial cell speed; bacteria with more flagella can move faster compared to cells with fewer flagella. One study demonstrated a 19% increase in bacterial speed in bacteria possessing four flagella in a viscous environment compared to cells with three flagella. The bacterial cells with greater motility may be deposited with higher density on the gastric epithelium, triggering a higher inflammatory response. It has been found that strains with greater motility increase the sialic acid-binding adhesion (SabA)-mediated interaction of H. pylori, providing a synergistic effect for pathological outcome severity in patients.

After infection, the toll-like receptor (TLR) 5 recognizes the flagellin composed of D0, D1, D2, and D3 domains. TLR5 recognition is important for the immunological events necessary for the inflammatory process. A recent study by Forstneric et al. demonstrated the role of flagellin in the TLR5 recognition evasion. In the study, the residues within the domain D0 play a crucial role in flagellin’s escape from TLR5 recognition.

Therefore, urease, bacterial shape, the number of flagella, and motility allow the bacteria to escape the harsh gastric conditions and help establish persistent infections.

3. Virulence Factors Associated with Colonization of Epithelial Surfaces

The outer membrane proteins like blood group antigen-binding adhesin (BabA), SabA, outer inflammatory protein (OipA), H. pylori outer membrane protein (HopQ), and other proteins interact with the receptors found on the host epithelial cells, playing a key role in pathological events of persistent infections (Table 1). This interaction also provides several benefits to infecting H. pylori strains. The interaction protects the bacterium from washing out during mucus shedding, provides nutrient access to the bacteria, and promotes delivery of bacterial toxins and other effector molecules to the host cells.

3.1. Blood Group Antigen-Binding Adhesin

BabA, an outer membrane adhesin protein, plays a crucial role in bacterial attachment, and it makes a significant contribution to cellular pathogenicity (reviewed by Ansari and Yamaoka). BabA is an important protein of outer membrane protein (OMP) family with an approximate molecular weight of around 75–80 kDa. Two closely related paralogs, BabB and BabC have been identified.

H. pylori adheres to the epithelium with the help of BabA as an adhesin on the bacterial surface that interacts with di-fucosylated glycan found on Leb and mono-fucosylated glycan found on H1-antigen, A-antigen, and B-antigen of blood groups O, A, and B respectively. Although the BabA-mediated attachment provides survival adaptation and persistent infections, the functions of BabB and BabC are not yet known. The bab gene sequence analysis revealed that there is variability in the middle sequence region and extensive 5′ and 3′ region conservation, particularly between babA and babB. The sequence variability in the middle region of babA suggests that this is the location of BabA’s receptor-binding function. The 5′ and 3′ conservation in bab gene sequences undergo RecA-dependent intragenomic recombination between these homologous genes (babA, babB and babC), resulting in chimeric genes that may provide benefits to the organisms. The formation of the chimeric gene babB/A has been shown to convert non-Leb binding strains to Leb binding strains, or it can abolish babA-dependent adhesion.

The BabA binding with Leb has been shown to enhance CagA translocation and induce VacA, γ-glutamyl transpeptidase, and cag-pathogenicity island (cagPAI)-independent double-strand breaks in the host cells. In Western countries, infection with BabA producing strains has been associated with an increased risk for peptic ulcer disease development. A recent study highlighted the adherence of strains with a high avidity mediated by BabA-positive pediatric ulcerogenic H. pylori strains.

Based on the binding preferences with ABO blood group antigens, the BabA-positive H. pylori strains can be of two types. The “specialists” prefer to bind only blood group O-specific glycans, while the “generalists” bind blood group O and blood group A and B-specific glycans. The capability of both specialist and generalist strains to bind with blood group O-specific glycans explains why people with blood group O are at a high risk for developing duodenal ulcer diseases.

3.2. Sialic Acid-Binding Adhesin

The OMP SabA binds to gangliosides with fucose substitutions of the N-acetyllactosamine like the dimeric sialyl-Lex antigen. SabA also binds to N-acetyllactosamine-based antigens with terminal α3-linked Neu5Ac, with preferential binding to gangliosides with long N-acetyllactosamine chains. Recently, minor SabA binding gangliosides of the human gastric mucosa, Neu5Aca3-neolactohexaosylceramide and Neu5Aca3-neolactooctaosylceramide, have been identified. They may provide new insight into the molecular basis for the H. pylori chronic infection in human hosts.

An enhanced H. pylori colonization density in Leb-negative individuals was reported based on interactions between SabA adhesin and sialylated gastric glycoconjugates. The sabA gene sequence can undergo homologous recombination with the homologous gene called sabB, and it can also happen to some extent with hopQ.

Several studies reported an association between sabA expression and an increased risk of chronic gastritis, intestinal metaplasia, corpus atrophy and even gastric cancer. H. pylori-mediated gastric inflammation was shown to alter the gastric mucosa glycosylation with an upregulation of sialyl-Lex antigens and promoting the SabA mediated bacterial attachment to the gastric mucosa. Therefore, increased expression of high-affinity SabA binding glycoconjugates in inflamed gastric epithelium supports enhanced adherence of SabA-positive H. pylori, allowing bacterial persistence and gastric pathogenicity establishment. The results of a study conducted by Mahadavi et al. suggest a close relationship between the presence of sabA, the cag-pathogenicity island, and babA. According to some authors, the combination of SabA with other virulence factors like OipA and BabA gives the best predictive model by which gastric cancer patients can be distinguished from duodenal ulcer patients and normal individuals.

3.3. Outer Inflammatory Protein (OipA)

OipA is another virulence protein belonging to the H. pylori OMP family, and it is encoded by the oipA gene. The number of CT dinucleotide repeats in the 5′ signal peptide regulates the expression of OipA via a slipped strand mispairing system. The status is designated as “on” when a functional protein is expressed, while expression of a non-functional protein is designated as “off”.

The strains expressing a functional OipA are reportedly involved in bacterial adherence to the gastric epithelial cells with mucosal damage and association with host cell apoptosis, interleukin (IL)-8 induction, duodenal ulcers, and gastric cancer development. A study report highlighted the oipA gene’s association with chronic gastritis development. Strains expressing functional OipA were most frequently isolated from patients with gastric cancer in Western countries.

Furthermore, the results of another study reported that patients infected with strains with “on” status oipA possess a higher risk for peptic ulcers and gastric cancer development rather than developing gastritis or functional dyspepsia. A recent study showed that enhanced adherence to epithelial cells and the translocation of CagA in the presence of functional cagPAI is exhibited by the OipA positive strains. The existence of oipA together with cagA have been suggested to contribute to proliferation and damage to the normal cellular integrity associated with β-catenin signaling. Moreover, H. pylori OipA was reported to reduce IL-10 expression and dendritic cell (DC) maturation, contributing to chronic H. pylori infection establishment.

3.4. Helicobacter Pylori Outer Membrane Protein (HopQ)

HopQ is another H. pylori OMP. Sequence analysis of hopQ from unrelated strains revealed two genotypes classified as type I and type II, which exhibit a high level of genetic diversity. H. pylori HopQ contributes to bacterial adherence to epithelial cells interacting with various members of the carcinoembryonic antigen-related cell adhesion molecules (CEACAM) family expressed on the gastric epithelium specifically during gastritis and gastric cancer development.

In 2005, Cao et al. reported that the H. pylori HopQ type I genotype is associated with increased peptic ulcer development in the US population. Consequently, another study also found a significant association of HopQ type I in gastric ulcers and in gastric cancer development. Similarly, studies also found an association between HopQ type II and gastric cancer development.

The recent studies highlighted that the interaction between HopQ and CEACAM contributes to gastric colonization and facilitates translocation of the CagA protein into the gastric epithelium to induce pathogenicity. A recent study showed that the interaction between HopQ and CEACAM plays a significant role in inhibiting immune cell activities. Moreover, the association of multiple types of H. pylori HopQ (type I and II) has been recently found in the development of B-cell non-Hodgkin lymphoma and HopQ type II with a higher prevalence.

Therefore, OMP adhesins provide bacterial attachment to host cells and provide an additional role in pathogenicity.

4.1. Cag-Pathogenicity Island (cagPAI)

H. pylori cagPAI is an approximately 40 kb long chromosomal region that contains up to 32 genes encoding a multicomponent bacterial type IV secretion system (T4SS) and an effector protein like CagA. The T4SS forms a syringe-like structure that makes contact with the host epithelium and translocates the effector protein CagA and peptidoglycan into the epithelium. Electron microscopy revealed T4SS to be a core structure of 41 nm protruding from the bacterial surface. At least 17 genes must be expressed to encode the intact T4SS for its essential functions, and 14 genes must be expressed to fully induce IL-8 secretion. The strains expressing the intact cagPAI are associated with the development of several disorders like chronic gastritis, peptic ulcer diseases, and gastric cancer. Moreover, a recent study found that the strains recovered from the ulcer patients contained a significantly higher prevalence of all individual genes and intact cagPAI compared to strains recovered from non-ulcer patients.

Some of the cagPAI components are essential for T4SS function or they are important for CagA translocation (Table 1). CagT is essential for translocation of the effector protein CagA into the epithelial cells, while others like CagY act as an immune-sensitive molecular regulator that modulates the immune response to promote bacterial persistence and alter T4SS function. Cagζ (Cag1), a membrane protein in T4SS, is closely associated with T4SS function, IL-8 expression induction, and CagA delivery to host cells. A recent study uncovered CagQ’s role as a membrane protein in T4SS for maintaining CagA expression and CagA-induced apoptotic effects.

Another T4SS component, CagL, a pilin-like component encoded by the cagL gene (HP0539), is expressed on the surface of H. pylori in a T4SS-dependent manner and in collaboration with the human integrin β1-containing receptors. In particular, integrin α5β1 is necessary for the CagA translocation. The tripeptide motif arginine-glycine-aspartic acid (RGD) of CagL at residues 76–78 together with the RGD helper sequence, which is a neighboring surface-exposed FEANE (phenylalanine-glutamic acid-alanine-asparagine-glutamic acid) motif was proposed to be essential for the interaction of T4SS with integrin receptors for CagA translocation into host cells. This RGD-dependent binding of CagL to integrins was also shown to trigger intracellular signaling pathways inducing cell pro-inflammatory responses that are CagA translocation-independent. Recent studies found an association of novel CagL variants with chronic gastritis and peptic ulcer disease (PUD) development. Particular polymorphisms upstream of the RGD motif at amino acid residues 58–62, called the CagL hypervariable motif (CagLHM), are correlated with severe disease progression in a geographically-dependent manner. Therefore, cagL deletion was shown to phenocopy complete cagPAI knockout in many respects because of its role as an essential T4SS component. This behavior was suggested due to the strain being unable to form a functioning T4SS in response to host cell contact without CagL. Therefore, in addition to CagA, the strain will not be able to translocate the peptidoglycan, DNA, or precursors of lipopolysaccharide into host cells. The results of a recent study demonstrated that in addition to playing a crucial role in the translocation of CagA, the H. pylori CagL may also be responsible for H. pylori-induced IL-8 expression via the transforming growth factor (TGF)-α activated epidermal growth factor-receptor (EGF-R) signaling pathway, H. pylori-induced hummingbird phenomena (elongation of the cells), and the bridging of the T4SS to its human target cells.

The effector protein CagA is 125–145 kDa. It is expressed by the highly virulent H. pylori strains possessing cagPAI, and it is absent from less virulent cagPAI negative strains. The synthesized CagA is translocated into the gastric epithelial cells via T4SS. Although H. pylori synthesizes an abundant amount of CagA, a relatively low amount of it is translocated inside the host epithelial cells. The translocated intracellular CagA levels are also regulated by autophagy and the ubiquitin-proteasome system, which degrades the translocated CagA. The biological activity of CagA is determined by the types and number of well-characterized EPIYA (glutamic acid-proline-isoleucine-tyrosine-alanine) sequences containing EPIYA-motifs at the C-terminal region. H. pylori isolates recovered from Western countries usually possess CagA with EPIYA-A, -B, and -C where the EPIYA-C region can be up to three units long, while the CagA in H. pylori strains recovered from the East Asian countries possess EPIYA-A, -B, and -D sequences. The first two EPIYA sequences, EPIYA-A and EPIYA-B, are carried by almost all CagA, and the third EPIYA sequence (either EPIYA-C in Western strains or EPIYA-D in East Asian strains) is associated with geographic, genotypic, and virulence characteristics. After its translocation into the host epithelial cells, the EPIYA-motifs of CagA undergo tyrosine (Y)-phosphorylation via various cellular kinases like Csk, c-Src, and c-Abl. The phosphorylated tyrosine interacts with the Src homology 2 phosphatase (SHP2) or the adapter protein Grb2 and hinders cell–cell adhesion, cellular proliferation, IL-8 expression, and cellular elongation via the activation of various cell signaling pathways like Ras-ERK MAP kinases (Rap1 → B-Raf → Erk) and Wnt-β-signaling. A recent study by Li et al. demonstrated that CagA stimulates YAP signaling pathway activation leading to gastric tumorigenesis in AGS cells. This in vitro result was also supported by the finding that H. pylori infection could enhance YAP expression activation in concert with E-cadherin suppression in chronic gastritis tissues infected with H. pylori compared to H. pylori negative patients.

The CagA with EPIYA-D motif has stronger binding affinity with SHP2 than the EPIYA-C motif. Therefore, the strains containing CagA with EPIYA-A, -B, and -D motifs are considered more virulent than strains containing CagA with EPIYA-A, -B, and -C motifs. In a recent meta-analysis, CagA with a single EPIYA-D motif was significantly associated with a 1.91 fold increased gastric cancer risk in Asia compared with one EPIYA-C motif, and the CagA with two or more EPIYA-C motifs (EPIYA-A, -B, -C, -C or EPIYA-A, -B, -C, -C, -C) was associated with a significantly higher risk for PUDs in Asian countries and gastric cancer (OR (odd ratio) = 3.28) in the US and Europe. In addition to the type of EPIYA-motifs, strains with amino acid polymorphism within the Western-specific EPIYA-B motif like EPIYT-B may influence CagA activity, reducing the ability to induce hummingbird phenomena and IL-8 expression conferring lower risk for gastric cancer and a higher risk for duodenal ulcer development. A recent study demonstrated that secreted H. pylori CagA can induce caudal type homeobox 1 (CDX1) expression, which is a homeobox transcription factor that plays an important role in human intestine development and maintenance. CDX1 activation promotes cell proliferation, invasion/migration, intestinalization of gastric epithelial cells, and stem cell-like phenotype induction leading to cancer development and failure of common gastric cancer chemotherapies. Recently, another study discovered CagA-mediated downregulation of heat shock protein 1 (HSP1) expression after H. pylori infection. CagA-dependent acute HSP1 suppression represses the host immune response, so H. pylori may escape from the immune response and enhance infection establishment. Although cagPAI positive H. pylori is considered as the strongest risk factor for the development of the gastroduodenal complications, the precise mechanism behind the development of severe complications is still not completely understood. Recently, a study has pointed out the role of H. pylori cagPAI in the expression of Lrig1 (leucine-rich repeats and Ig-like domains 1) in a CagA and CagE-dependent manner. Lrig1 is a transmembrane protein that acts as an intestinal stem/progenitor cell marker. The study demonstrated a significant increase in Lrig1-positive cells in the premalignant lesions (atrophic gastritis and intestinal metaplasia) in the antrum and corpus compared with that in the normal mucosa and stomach lining, which indicates the possible contribution of these cells to the ability of H. pylori to cause injury and promote carcinogenesis in the stomach.

4.2. Vacuolating Cytotoxin (VacA)

VacA is an important H. pylori pore-forming cytotoxin that plays a crucial role in pathogenicity by interacting with gastric epithelial cells. The ability of this toxin to induce vacuole formation in eukaryotic cells led to it being named VacA. Initially, VacA is formed as a 140 kDa pro-toxin that is secreted through the auto-transporter pathway. The mature 88 kDa secreted toxin undergoes limited proteolysis to yield two fragments: p33 and p55.

The three heterogenic regions of VacA have significant sequence variation. The “s” region represents the sequence variation in the amino-terminal signal sequence. The “m” region represents the amino acid variation located in the middle of the p55 domain. The “i” region was recently identified in a survey conducted in the Iranian population, and it represents the amino acid variation in the intermediate region located between the “s“ and “m“ region in the p33 domain. The sequence variation of VacA isolated from the clinical H. pylori isolates indicates the s1a, s1b, s1c, and s2 sub-families of the “s“ region. m1 and m2 are sub-families of the “m“ region. i1, i2, and i3 are sub-families of the “i“ region. The allelic diversity was reviewed in detail by Tran et al..

The studies have revealed that the combination of different sequences in the three regions can determine the capability of vacuolation. Moreover, the genotype possessing the combination s1/m1 exhibits high vacuolating activity, and the genotype s1/m2 has intermediate activity. On the other hand, no vacuolating activity was shown by the genotype s2/m2. This finding indicates that the vacuolating capability of VacA with the s2 genotype is lower than the s1 genotype. The s2 region contains an additional 12 amino acids in the N-terminal sequence causing the predominant hydrophilic nature compared to the strongly hydrophobic s1 region, which most probably causes impairment in the anion-selective channel formation and cell vacuolation. The lower vacuolating activity was also supported by the fact that VacA export with the s2 genotype from the cytoplasmic membrane to the periplasmic space is less efficient compared to s1 genotypes. The strains with the s1 sequence were reported to secrete higher amounts of VacA that may be caused by elevated vacA transcription than s2 type strains. Therefore, these differences could cause the higher activity of vacuolation by strains possessing VacA with the s1/m1 genotype.

In clinical H. pylori isolates from ulcer patients, a higher prevalence of VacA with s1a, m1, and i1 genotypes have been detected compared to patients with non-ulcer diseases. A meta-analysis conducted in Western populations found that the individuals pose an increased risk for gastric cancer development if they are infected with H. pylori harboring vacA with s1 or m1 regions. On the other hand, in Middle Asia and Middle East Asia, patients infected with vacA i1 type harboring H. pylori are associated with a high risk for gastric cancer development (OR = 10.9–15.0). The antibody against VacA is associated with an increased risk for gastric cancer development. A recent meta-analysis conducted by Li et al. observed an association of a VacA antibody with peptic ulcer disease and gastric cancer risk, which suggests the role of VacA as a biomarker for the prediction of peptic ulcer disease and gastric cancer risk. Furthermore, a strong antibody response to H. pylori VacA is significantly associated with the risk of extra-gastric diseases such as colorectal cancer development, particularly in African Americans.

VacA plays several roles in cellular pathogenicity (Table 1), and it is considered a multifunctional toxin eliciting multiple effects on host cells like vacuolization and cell necrosis. Numerous studies have also shown cell apoptosis induction by VagA through the mitochondrial pathway in gastric epithelial cells. An additional apoptotic potential was elaborated in a study, which provided novel evidence that VacA triggers the endoplasmic reticulum stress response to activate autophagy and increased cellular death of AGS cells. The studies have found that the 148 amino acid segment localized at the middle region exploits the cell binding specificity of VacA, and strains harboring VacA have the best survival for H. pylori inside the gastric epithelial cells. A recent study reported that the VacA promotes bacterial survival independent of CagA accumulation. This survival efficacy was determined in a recent study where the H. pylori VacA can play an important role in a transient receptor potential membrane channel mucolopin 1 (TRPML1) activity that inhibits the lysosomal and autophagic killing of bacterial cells to promote the establishment of an intracellular niche that allows for bacterial survival.

4.3. High-Temperature Requirement Protein (HtrA)

Organisms are continuously exposed to oxidative and heat stress that can kill them. However, organisms tolerate these stresses and degrade intracellular irreversibly misfolded proteins that may be toxic to the organisms. The protease HtrA plays an important role in neutralizing the effects of these stress responses in both prokaryotes and eukaryotes like humans. When encountering denatured or misfolded proteins, HtrA undergoes oligomerization and conformational changes to switch to proteolytic activity (Table 1). The HtrA protein is generally transported in the periplasmic space, where they form proteolytically active oligomers which exhibit both protein quality control and chaperone functions. However, the HtrA protein is transported extracellularly in H. pylori. H. pylori HtrA is highly resistant to temperature and pH variations, which indicates its ability for adaptation and causing colonization and persistent infection even in harsh stomach conditions.

The extracellularly exported HtrA enables the bacteria to deliver the virulence factor like CagA to the basolateral membrane of host cells despite infection initiation at the apical side. The serine protease activity of the H. pylori HtrA protein was found to cleave the proteins of tight junctions like occludin, claudin-8, and the E-cadherin molecules on the gastric epithelial cells, which are important adherens junction proteins and tumor suppressors. Moreover, their destruction has been strongly connected with the progression and metastasis of gastric tumors in humans. The findings have also suggested that the HtrA-mediated E-cadherin destruction causes the disruption of the epithelial barrier and transmigration of H. pylori across the polarized gastric epithelial linings. The results of a recent study found that the htrA gene in H. pylori is one of the highly conserved genes to be found in isolates from Europe, Asia, North America, and South America. This conservation suggests that there is little or no effect on the htrA gene region over the course of H. pylori and human co-evolution like the H. pylori MLST housekeeping genes.

4.4. Outer Membrane Vesicles

Outer membrane vesicles (OMVs) are characterized as blebs of 20–300 nm in diameter which are naturally secreted by several Gram-negative bacteria including H. pylori during their growth in logarithmic phase. Since OMVs are released from the outer membrane of bacteria, they contain several outer membrane specific phospholipids like phosphatidylglycerol (PG), phosphatidylethanolamine (PE), lyso-PE (LPE), phosphatidylcholine (PC), lyso-PC (LPC), cardiolipin, lipopolysaccharides, and several bacterial virulence factors like adhesins, proteases, and toxins. After their release, these OMVs are taken up by gastric epithelial cells via clathrin-dependent endocytosis or a clathrin-independent mechanism (lipid raft-mediated mechanism). Moreover, the H. pylori OMVs have been reported to protect the pathogen from the toxic effect of the reactive oxygen species respiratory burst.

OMVs have been detected intracellularly and extracellularly in gastric biopsy specimens. In addition to protecting the pathogen, they have been suggested to promote infection, impair cellular function, and modulate host immune defenses via immunosuppressive cytokine IL-10 production by human peripheral blood mononuclear cells and via apoptosis in Jurkat T cells. Similarly, H. pylori OMVs have been also found to induce dendritic cells by upregulating the expression of co-stimulatory molecules and expression of more heme oxygenase-1 via the activation of Akt-Nrf2 and mTOR-κB Kinase–NF-κB pathways. Moreover, the studies have detected H. pylori OMVs in the gastric juice of patients with gastric cancer. In a recent study conducted by Choi et al., the gastric juice collected from gastric cancer patients showed a significantly higher amount of both H. pylori cells and the H. pylori-derived OMVs compared to healthy controls. Furthermore, these H. pylori-derived OMVs also induced inflammation in the mouse model, inducing gastric cancer development.

4.5. H. pylori γ-Glutamyl Transpeptidase

H. pylori γ-glutamyl transpeptidase (gGT) is an enzyme that catalyzes the transpeptidation and hydrolysis of the γ-glutamyl moiety of glutathione and glutathione-conjugated compounds to amino acids. Although gGT is an essential component for H. pylori infection in mice, the deletion of gGT has no inhibitory effect on the ability to grow on the culture media. A study using two distinct animal models (mice and piglets) with H. pylori infection indicates that in infection with gGT-deficient strains, the colonization is reduced in comparison to the infection with the isogenic wild type strains. The consistent results in these two animal models also suggest that the presence of gGT provides at least some advantage to allow H. pylori to infect epithelial cells. The study suggests that H. pylori gGT provides a growth advantage within the gut by salvaging extracellular glutathione to obtain cysteine for subsequent protein synthesis and the activity is greatest at a neutral pH. Recently, a similar result of significantly higher colonization with gGT-positive strains was suggested by Wustner et al.. Moreover, a recent study described the novel role of H. pylori gGT in autophagy regulation and bacterial internalization in human gastric cells, which suggests the possible role of gGT in the protection of bacteria to commence a persistent infection.

H. pylori gGT induces apoptosis, inhibits gastric cell proliferation, arrests the cell cycle, and generates reactive oxygen species and the significantly higher activity of gGT has been demonstrated in strains isolated from patients with peptic ulcer disease and gastric cancer, which suggests the possible role of gGT in the contribution to severe pathogenicity. Furthermore, a recent study revealed the role of gGT in accentuating VacA-dependent vacuolation of epithelial cells. The enhancement of vacuolation by gGT is carried out by the hydrolysis of extracellular glutamine, thereby releasing ammonia which accentuates VacA-dependent vacuolation. This discovery suggests why H. pylori with higher activity of gGT exhibits more severe gastro-duodenal diseases.

5. Other Virulence Factors Playing a Role in Triggering Pathogenicity

Despite of the above-mentioned well-characterized virulence factors, several studies have depicted the association of other virulence factors in the severity of gastric complications. A recent study conducted by Capitani et al. described the possible role of the HP1454, a secreted protein and component of OMVs, in the Th1 and Th17-mediated inflammatory response in the chronic H. pylori infection and associated gastric cancer. In addition to cagPAI encoding the T4SS, another putative gene cluster with low G + C content of around 35% encoding the T4SS in H. pylori is located within the integrating conjugative elements (ICE). Recently, we reported the role of the specific variants of H. pylori ICE T4SS (ICEhptfs) in pathogenicity. In the study, the cagPAI-mediated acute inflammation in the antrum and body was ICEhptfs-dependent, and this dependency was also attributed to the higher atrophy score in antrum. The expression of cholesterol glycosyl-transferase (CGT) that depletes cholesterol in infected gastric epithelial cells blocks IFN-gamma signaling and protects bacteria from the inflammatory response. This discovery suggests a novel mechanism of H. pylori CGT utilization for the promotion of gastric carcinogenesis.

6. Whole Genome Sequencing and Genome Wide Association Studies (GWAS) Approach for Virulence Determination

In recent years, the whole genome sequencing (WGS)-based approach from cultured bacterial isolates has emerged as one of the most comprehensive tools for surveillance study, drug resistance determination, and evolutionary analysis of infectious diseases. This is due to improved sequencing technologies, the user friendly nature, easy availability of reagents, improved accuracy of up to 93%, reasonably lower costs (150EUR per 5 MB genome by Illumina MiSeq), and faster results (nine days versus 21 days) compared to traditional DNA sequencing. In addition to these benefits, the WGS also offers a more comprehensive and accurate tool for genome analysis.

Recently, the WGS has been used to characterize a variety of pathogens to determine the novel or existing virulence factors. In a study, Hurley et al. performed WGS-based characterization of 100 Listeria monocytogenes strains to determine disease epidemiology, the presence of drug resistance genes, and to determine virulence factors. Similarly, another study was conducted by Edwards et al. to characterize the putative virulence factors in Plesiomonas shigelloides. Furthermore, Aly et al. used a WGS-based study to identify genes associated with biofilm formation, antibiotic resistance, and pathogenicity. The results of these studies clearly suggest that WGS-based approaches are an advancement over traditional Sanger sequencing.

Currently, the WGS tool is mostly being used to determine the presence of antibiotic resistance genes in H. pylori because of the absence of the resistance determinants in plasmids, transposons, or integrons. However, this approach has recently gained popularity in virulence determination. In a recent study, Ogawa et al. performed WGS of 43 clinical isolates H. pylori (17 chronic gastritis, eight gastric ulcers, eight duodenal ulcers, and 10 gastric cancers). Full cagL and cagI sequences were analyzed for single nucleotide variation and amino acid changes. The WGS results identified several putative novel variants of CagL and CagI sequences, proving its usefulness in virulence determination. The search for the genetic basis of susceptibility to particular diseases using populations with the specific diseases and matched controls and GWAS has become popular in human genetics. Recently, this novel state of the art methodology was used in H. pylori to search for the novel virulence factors using genomic information from strains isolated from gastric cancer and matched controls like isolates from the duodenal ulcers. Berthenet et al. used GWAS in their recent study to illustrate the association of the presence of the cagPAI genes cag11 (cagV), cag12 (cagU), and cag 20 (cagI) in H. pylori isolated from patients with gastric cancer.

H. pylori and Microbiota in Gastric Carcinogenesis

H. pylori promotes carcinogenesis by influencing the composition of the microbial population (microbiota) in the stomach; however, the mechanism is not fully understood. The precise balance of commensal microbiota in the gastrointestinal tract plays a role in the regulation of the host mucosal immune response, efficient killing of potential pathogens, and carcinogenesis. Studies have suggested that some of the microbes including Escherichia coli, Lactobacillus spp., Nitrospirae spp., Clostridium spp., Veillonella spp., Haemophilus spp., and Staphylococcus spp. that convert nitrogen compounds to potentially carcinogenic N-nitroso compounds in gastric fluid enhance cancer development, whereas oral commensals such as Streptococcus spp., Prevotella spp., and Neisseria spp. are associated with a lower risk for gastric cancer development. In contrast, other oral microbes such as Pasteurella stomatis, Spodoptera exigua, Parvimonas micra, Streptococcus anginosus, and Dialister pneumosintes exhibit a strong co-occurrence in gastric carcinogenesis. In a study, Wang et al. observed an abundant presence of five bacterial genera (Lactobacillus spp., Escherichia coli, Shigella spp., Nitrospirae spp., Burkholderia fungorum, and Lachnospiraceae spp.) in gastric cancer patients, where Nirospirae spp. was observed in all gastric cancer patients but not in chronic gastritis patients. A recent study has described the alteration in the relative abundances of the dominant phyla Bacteroidetes, Firmicutes, and Proteobacteria in the fecal microbiota of subjects with H. pylori-positive gastric precancerous lesions, which suggests the possible association of these phyla with the progression of H. pylori related gastric lesions. The co-excluding and co-occurring interactions of H. pylori with Methylobacillus and Arthrobacter, respectively, in severe gastritis has been observed, whereas co-excluding interactions with members of the phylum Firmicutes (Ruminococcus, Bacillales, and Lactobacillus) and co-occurrence interactions with Prevotella, Moryella, and another helicobacter (H. ganmani) have been reported. Therefore, site-specific gastric microbiota that colonize the tumor microenvironment are an important factor for carcinogenesis and its progression.

7. Conclusions

This study depicts the importance of several virulence factors playing a role in the severity of gastric complications. H. pylori infections contribute the highest risk for developing severe gastric diseases. Therefore, the virulence factors characterized in the isolated strains will provide a clue for the disease prediction in the populations. Currently, WGS and GWAS-based investigations and their meaningful results for the putative virulence and drug resistance determinants have encouraged researchers to perform more extensive and multidisciplinary efforts for better understanding of virulence factor involvement in the onset and progression of gastric complications.

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    Not in our library10.1038/srep23264

  68. 68.

    Tegtmeyer N., Moodley Y., Yamaoka Y., Pernitzsch S.R., Schmidt V., Traverso F.R., Schmidt T.P., Rad R., Yeoh K.G., Bow H., et al. Characterization of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA. Mol. Microbiol. 2016;99:925-944.

    Not in our library10.1111/mmi.13276

  69. 69.

    Chan A.O. E-cadherin in gastric cancer. World J. Gastroenterol. 2006;12:199-203.

    Not in our library10.3748/wjg.v12.i2.199

  70. 70.

    Tegtmeyer N., Wessler S., Necchi V., Rohde M., Harrer A., Rau T.T., Asche C.I., Boehm M., Loessner H., Figueiredo C., et al. Helicobacter pylori Employs a Unique Basolateral Type IV Secretion Mechanism for CagA Delivery. Cell Host Microbe. 2017;22:552-560.e5.

    Not in our library10.1016/j.chom.2017.09.005

  71. 71.

    Wessler S., Backert S. A novel basolateral type IV secretion model for the CagA oncoprotein of Helicobacter pylori. Microb. Cell. 2018;5:60-62.

    Not in our library10.15698/mic2018.01.611

  72. 72.

    Lekmeechai S., Su Y.C., Brant M., Alvarado-Kristensson M., Vallström A., Obi I., Arnqvist A., Riesbeck K. Helicobacter pylori outer membrane vesicles protect the pathogen from reactive oxygen species of the respiratory burst. Front. Microbiol. 2018;9:1837.

    Not in our library10.3389/fmicb.2018.01837

  73. 73.

    Macdonald I.A., Kuehn M.J. Offense and defense: Microbial membrane vesicles play both ways. Res. Microbiol. 2012;163:607-618.

    Not in our library10.1016/j.resmic.2012.10.020

  74. 74.

    Laughlin R.C., Mickum M., Rowin K., Adams L.G., Alaniz R.C. Altered host immune responses to membrane vesicles from Salmonella and gram-negative pathogens. Vaccine. 2015;33:5012-5019.

    Not in our library10.1016/j.vaccine.2015.05.014

  75. 75.

    Ko S.H., Rho D.J., Jeon J.I., Kim Y.J., Woo H.A., Kim N., Kim J.M. Crude preparations of Helicobacter pylori outer membrane vesicles induce upregulation of Heme Oxygenase-1 via activating Akt-Nrf2 and mTOR-IkappaB kinase-NF-kappaB pathways in dendritic cells. Infect. Immun. 2016;84:2162-2174.

    Not in our library10.1128/iai.00190-16

  76. 76.

    Shibayama K., Kamachi K., Nagata N., Yagi T., Nada T., Doi Y., Shibata N., Yokoyama K., Yamane K., Kato H., et al. A novel apoptosis-inducing protein from Helicobacter pylori. Mol. Microbiol. 2003;l47:443-451.

    Not in our library10.1046/j.1365-2958.2003.03305.x

  77. 77.

    Kim K.M., Lee S.G., Park M.G., Song J.Y., Kang H.L., Lee W.K., Cho M.J., Rhee K.H., Youn H.S., Baik S.C. γ-Glutamyltranspeptidase of Helicobacter pylori induces mitochondria-mediated apoptosis in AGS cells. Biochem. Biophys. Res. Commun. 2007;355:562-567.

    Not in our library10.1016/j.bbrc.2007.02.021

  78. 78.

    Valenzuela M., Bravo D., Canales J., Sanhueza C., Díaz N., Almarza O., Toledo H., Quest A.F.G. Helicobacter pylori-induced loss of survivin and gastric cell viability is attributable to secreted bacterial gamma-glutamyl transpeptidase activity. J. Infect. Dis. 2013;208:1131-1141.

    Not in our library10.1093/infdis/jit286

  79. 79.

    Ling S.S.M., Khoo L.H.B., Hwang L.A., Yeoh K.G., Ho B. Instrumental role of Helicobacter pylori γ-glutamyl transpeptidase in VacA-dependent vacuolation in gastric epithelial cells. PLoS ONE. 2015;10:e0131460.

    Not in our library10.1371/journal.pone.0131460

  80. 80.

    Odenbreit S. Adherence properties of Helicobacter pylori: Impact on pathogenesis and adaptation to the host. Int. J. Med. Microbiol. 2005;295:317-324.

    Not in our library10.1016/j.ijmm.2005.06.003

  81. 81.

    Rhen M., Eriksson S., Clements M., Bergström S., Normark S.J. The basis of persistent bacterial infections. Trends Microbiol. 2003;11:80-86.

    Not in our library10.1016/s0966-842x(02)00038-0

  82. 82.

    Aspholm M., Kalia A., Ruhl S., Schedin S., Arnqvist A., Lindén S., Sjöström R., Gerhard M., Semino-Mora C., Dubois A., et al. Helicobacter pylori adhesion to carbohydrates. Methods Enzymol. 2006;417:293-339.

    Not in our library10.1016/s0076-6879(06)17020-2

  83. 83.

    Ilver D., Arnqvist A., Ogren J., Frick I.M., Kersulyte D., Incecik E.T., Berg D.E., Covacci A., Engstrand L., Borén T. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science. 1998;279:373-377.

    Not in our library10.1126/science.279.5349.373

  84. 84.

    Pride D.T., Blaser M.J. Concerted evolution between duplicated genetic elements in Helicobacter pylori. J. Mol. Biol. 2002;316:629-642.

    Not in our library10.1006/jmbi.2001.5311

  85. 85.

    Borén T., Falk P., Roth K.A., Larson G., Normark S. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science. 1993;262:1892-1895.

    Not in our library10.1126/science.8018146

  86. 86.

    Hennig E.E., Mernaugh R., Edl J., Cao P., Cover T.L. Heterogeneity among Helicobacter pylori strains in expression of the outer membrane protein BabA. Infect. Immun. 2004;72:3429-3435.

    Not in our library10.1128/iai.72.6.3429-3435.2004

  87. 87.

    Aspholm-Hurtig M., Dailide G., Lahmann M., Kalia A., Ilver D., Roche N., Vikström S., Sjöström R., Lindén S., Bäckström A., et al. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science. 2004;305:519-522.

    Not in our library10.1126/science.1098801

  88. 88.

    Pride D.T., Meinersmann R.J., Blaser M.J. Allelic Variation within Helicobacter pylori babA and babB. Infect. Immun. 2001;69:1160-1171.

    Not in our library10.1128/iai.69.2.1160-1171.2001

  89. 89.

    Goodwin A.C., Weinberger D.M., Ford C.B., Nelson J.C., Snider J.D., Hall J.D., Paules C.I., Peek R.M., Forsyth M.H. Expression of the Helicobacter pylori adhesin SabA is controlled via phase variation and the ArsRS signal transduction system. Microbiology. 2008;154:2231-2240.

    Not in our library10.1099/mic.0.2007/016055-0

  90. 90.

    Solnick J.V., Hansen L.M., Salama N.R., Boonjakuakul J.K., Syvanen M. Modification of Helicobacter pylori outer membrane protein expression during experimental infection of rhesus macaques. Proc. Natl. Acad. Sci. USA. 2004;101:2106-2111.

    Not in our library10.1073/pnas.0308573100

  91. 91.

    Gerhard M., Lehn N., Neumayer N., Borén T., Rad R., Schepp W., Miehlke S., Classen M., Prinz C. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc. Natl. Acad. Sci. USA. 1999;96:12778-12783.

    Not in our library10.1073/pnas.96.22.12778

  92. 92.

    Olfat F.O., Zheng Q., Oleastro M., Voland P., Borén T., Karttunen R., Engstrand L., Rad R., Prinz C., Gerhard M. Correlation of the Helicobacter pylori adherence factor BabA with duodenal ulcer disease in four European countries. FEMS Immunol. Med. Microbiol. 2005;44:151-156.

    Not in our library10.1016/j.femsim.2004.10.010

  93. 93.

    Quintana-Hayashi M.P., Rocha R., Padra M., Thorell A., Jin C., Karlsson N.G., Roxo-Rosa M., Oleastro M., Lindén S.K. BabA-mediated adherence of pediatric ulcerogenic H. pylori strains to gastric mucins at neutral and acidic pH. Virulence. 2018;9:1699-1717.

    Not in our library10.1080/21505594.2018.1532243

  94. 94.

    Benktander J., Barone A., Johansson M.M., Teneberg S. Helicobacter pylori SabA binding gangliosides of human stomach. Virulence. 2018;9:738-751.

    Not in our library10.1080/21505594.2018.1440171

  95. 95.

    Sheu B.S., Odenbreit S., Hung K.H., Liu C.P., Sheu S.M., Yang H.B., Wu J.J. Interaction between host gastric Sialy-Lewis-X and H. pylori SabA enhances H. pylori density in patients lacking gastric Lewis B antigen. Am. J. Gastroenterol. 2006;101:36-44.

    Not in our library10.1111/j.1572-0241.2006.00358.x

  96. 96.

    Talarico S., Whitefeld S.E., Fero J., Haas R., Salama N.R. Regulation of Helicobacter pylori adherence by gene conversion. Mol. Microbiol. 2012;84:1050-1061.

    Not in our library10.1111/j.1365-2958.2012.08073.x

  97. 97.

    Yamaoka Y., Ojo O., Fujimoto S., Odenbreit S., Haas R., Gutierrez O., El-Zimaity H.M., Reddy R., Arnqvist A., Graham D.Y. Helicobacter pylori outer membrane proteins and gastroduodenal disease. Gut. 2006;55:775-781.

    Not in our library10.1136/gut.2005.083014

  98. 98.

    Yanai A., Maeda S., Hikiba Y., Shibata W., Ohmae T., Hirata Y., Ogura K., Yoshida H., Omata M. Clinical relevance of Helicobacter pylori sabA genotype in Japanese clinical isolates. J. Gastroenterol. Hepatol. 2007;22:2228-2232.

    Not in our library10.1111/j.1440-1746.2007.04831.x

  99. 99.

    Gharibi S., Falsafi T., Alebouyeh M., Farzi N., Vaziri F., Zali M.R. Relationship between histopathological status of the Helicobacter pylori infected patients and proteases of H. pylori in isolates carrying diverse virulence genotypes. Microb. Pathog. 2017;110:100-106.

    Not in our library10.1016/j.micpath.2017.06.023

  100. 100.

    Mahdavi J., Sondén B., Hurtig M., Olfat F.O., Forsberg L., Roche N., Ångström J., Larsson T., Teneberg S., Karlsson K.A. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science. 2002;297:573-578.

    Not in our library10.1126/science.1069076

  101. 101.

    Ota H., Nakayama J., Momose M., Hayama M., Akamatsu T., Katsuyama T., Graham D.Y., Genta R.M. Helicobacter pylori infection produces reversible glycosylation changes to gastric mucins. Virchows Arch. 1998;433:419-426.

    Not in our library10.1007/s004280050269

  102. 102.

    Su Y.L., Huang H.L., Huang B.S., Chen P.C., Chen C.S., Wang H.L., Lin P.H., Chieh M.S., Wu J.J., Yang J.C., et al. Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer. Sci. Rep. 2016;6:36442.

    Not in our library10.1038/srep36442

  103. 103.
    A Mr 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori · 2000
    Not checked
  104. 104.

    Horridge D.N., Begley A.A., Kim J., Aravindan N., Fan K., Forsyth M.H. Outer inflammatory protein a (OipA) of Helicobacter pylori is regulated by host cell contact and mediates CagA translocation and interleukin-8 response only in the presence of a functional cag pathogenicity island type IV secretion system. Pathog. Dis. 2017;75:ftx113.

    Not in our library10.1093/femspd/ftx113

  105. 105.

    Yamaoka Y., Kita M., Kodama T., Imamura S., Ohno T., Sawai N., Ishimaru A., Imanishi J., Graham D.Y. Helicobacter pylori infection in mice: Role of outer membrane proteins in colonization and inflammation. Gastroenterology. 2002;123:1992-2004.

    Not in our library10.1053/gast.2002.37074

  106. 106.

    Braga L.L.B.C., Batista M.H.R., de Azevedo O.G.R., da Silva Costa K.C., Gomes A.D., Rocha G.A., Queiroz D.M.M. oipA “on” status of Helicobacter pylori is associated with gastric cancer in NorthEastern Brazil. BMC Cancer. 2019;19:48.

    Not in our library10.1186/s12885-018-5249-x

  107. 107.

    Sallas M.L., dos Santos M.P., Orcini W.A., David E.B., Peruquetti R.L., Payão S.L.M., Rasmussen L.T. Status (on/off) of oipA gene: Their associations with gastritis and gastric cancer and geographic origins. Arch. Microbiol. 2019;201:93-97.

    Not in our library10.1007/s00203-018-1580-5

  108. 108.

    Liu J., He C., Chen M., Wang Z., Xing C., Yuan Y. Association of presence/absence and on/off patterns of Helicobacter pylori oipA gene with peptic ulcer disease and gastric cancer risks: A meta-analysis. BMC Infect. Dis. 2013;13:555.

    Not in our library10.1186/1471-2334-13-555

  109. 109.

    Franco A.T., Johnston E., Krishna U., Yamaoka Y., Israel D.A., Nagy T.A., Wroblewski L.E., Piazuelo M.B., Correa P., Peek R.M. Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors. Cancer Res. 2008;68:379-387.

    Not in our library10.1158/0008-5472.can-07-0824

  110. 110.

    Yamaoka Y. Mechanisms of disease: Helicobacter pylori virulence factors. Nat. Rev. Gastroenterol. Hepatol. 2010;7:629-641.

    Not in our library10.1038/nrgastro.2010.154

  111. 111.

    Teymournejad O., Mobarez A.M., Hassan Z.M., Moazzeni S.M., Ahmadabad H.N. In vitro suppression of dendritic cells by Helicobacter pylori OipA. Helicobacter. 2014;19:136-143.

    Not in our library10.1111/hel.12107

  112. 112.

    Backert S., Selbach M. Role of type IV secretion in Helicobacter pylori pathogenesis. Cell. Microbiol. 2008;10:1573-1581.

    Not in our library10.1111/j.1462-5822.2008.01156.x

  113. 113.

    Cao P., Cover T.L. Two different families of hopQ alleles in Helicobacter pylori. J. Clin. Microbiol. 2002;40:4504-4511.

    Not in our library10.1128/jcm.40.12.4504-4511.2002

  114. 114.

    Koniger V., Holsten L., Harrison U., Busch B., Loell E., Zhao Q., Bonsor D.A., Roth A., Kengmo-Tchoupa A., Smith S.I., et al. Helicobacter pylori exploits human CEACAMs via HopQ fot adherence and translocation of CagA. Nat. Microbiol. 2016;2:16188.

    Not in our library10.1038/nmicrobiol.2016.188

  115. 115.

    Feige M.H., Sokolova O., Pickenhahn A., Maubach G., Naumann M. HopQ impacts the integrin alpha5beta1-independent NF-kappaB activation by Helicobacter pylori in CEACAM expressing cells. Int. J. Med. Microbiol. 2018;308:527-533.

    Not in our library10.1016/j.ijmm.2018.05.003

  116. 116.

    Bonsor D.A., Zhao Q., Schmidinger B., Weiss E., Wang J., Deredge D., Beadenkopf R., Dow B., Fischer W., Beckett D., et al. The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA. EMBO J. 2018;37:e98664.

    Not in our library10.15252/embj.201798664

  117. 117.

    Cao P., Lee K.J., Blaser M.J., Cover T.L. Analysis of hopQ alleles in East Asian and Western strains of Helicobacter pylori. FEMS Microbiol. Lett. 2005;251:37-43.

    Not in our library10.1016/j.femsle.2005.07.023

  118. 118.

    Leylabadlo H.E., Yekani M., Ghotaslou R. Helicobacter pylori hopQ alleles (type I and II) in gastric cancer. Biomed. Rep. 2016;4:601-604.

    Not in our library10.3892/br.2016.634

  119. 119.

    Yakoob J., Abbas Z., Khan R., Salim S.A., Awan S., Abrar A., Jafri W. Helicobacter pylori outer membrane protein Q allele distribution is associated with distinct pathologies in Pakistan. Infect. Genet. Evol. 2016;37:57-62.

    Not in our library10.1016/j.meegid.2015.10.027

  120. 120.

    Abadi A.T.B., Mobarez A.M. High Prevalence of Helicobacter pylori hopQ II Genotype Isolated from Iranian Patients with Gastroduodenal Disorders. J. Pathog. 2014;2014:871601.

    Not in our library10.1155/2014/871601

  121. 121.

    Javaheri A., Kruse T., Moonens K., Mejias-Luque R., Debraekeleer A., Asche C.I., Tegtmeyer N., Kalali B., Bach N.C., Sieber S.A., et al. Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat. Microbiol. 2016;2:16189.

    Not in our library10.1038/nmicrobiol.2016.189

  122. 122.

    Grzeszczuk M.J., Bocian-Ostrzycka K.M., Banaśa A.M., Roszczenko-Jasinska P., Malinowska A., Stralova H., Haas R., Meyer T.F., Jagusztyn-Krynick E.K. Thiol-oxidoreductase HP0231 of Helicobacter pylori impacts HopQ-dependent CagA translocation. Int. J. Med. Microbiol. 2018;308:977-985.

    Not in our library10.1016/j.ijmm.2018.08.002

  123. 123.

    Yakoob J., Abbas Z., Ahmad Z., Tariq K., Awan S., Mustafa K., Khan R. Gastric lymphoma: Association with Helicobacter pylori outer membrane protein Q (HopQ) and cytotoxic-pathogenicity activity island (CPAI) genes. Epidemiol. Infect. 2017;145:3468-3476.

    Not in our library10.1017/s0950268817002023

  124. 124.

    Schuelein R., Everingham P., Kwok T. Integrin-mediated type IV secretion by Helicobacter: What makes it tick? Trends Microbiol. 2011;19:211-216.

    Not in our library10.1016/j.tim.2011.01.010

  125. 125.

    Backert S., Tegtmeyer N., Fischer W. Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. Future Microbiol. 2015;10:955-965.

    Not in our library10.2217/fmb.15.32

  126. 126.

    Frick-Cheng A.E., Pyburn T.M., Voss B.J., McDonald W.H., Ohi M.D., Cover T.L. Molecular and structural analysis of the Helicobacter pylori cag type IV secretion system core complex. mBio. 2016;7:e02001-e02015.

    Not in our library10.1128/mbio.02001-15

  127. 127.

    Nguyen L.T., Uchida T., Tsukamoto Y., Trinh T.D., Ta L., Mai H.B., Le H.S., Ho D.Q., Hoang H.H., Matsuhisa T., et al. Clinical relevance of cagPAI intactness in Helicobacter pylori isolates from Vietnam. Eur. J. Clin. Microbiol. Inf. Dis. 2010;29:651-660.

    Not in our library10.1007/s10096-010-0909-z

  128. 128.

    Sanchez-Zauco N.A., Torres J., Perez-Figueroa G.E., Alvarez-Arellano L., Camorlinga-Ponce M., Gómez A., Giono-Cerezo S., Maldonado-Bernal C. Impact of cagPAI and T4SS on the Inflammatory Response of Human Neutrophils to Helicobacter pylori Infection. PLoS ONE. 2013;8:e64623.

    Not in our library10.1371/journal.pone.0064623

  129. 129.

    Wroblewski L.E., Peek R.M. Helicobacter pylori: Pathogenic enablers-toxic relationships in the stomach. Nat. Rev. Gastroenterol. Hepatol. 2016;13:317-318.

    Not in our library10.1038/nrgastro.2016.68

  130. 130.

    Ahmadzadeh A., Ghalehnoei H., Farzi N., Yadegar A., Alebouyeh M., Aghdaei H.A., Molaei M., Zali M.R., Pour Hossein Gholi M.A. Association of CagPAI integrity with severeness of Helicobacter pylori infection in patients with gastritis. Pathol. Biol. 2015;63:252-257.

    Not in our library10.1016/j.patbio.2015.09.004

  131. 131.

    Kauser F., Khan A.A., Hussain M.A., Carroll I.M., Ahmad N., Tiwari S., Shouche Y., Das B., Alam M., Ali S.M., et al. The cag pathogenicity island of Helicobacter pylori is disrupted in the majority of patient isolates from different human populations. J. Clin. Microbiol. 2004;42:5302-5308.

    Not in our library10.1128/jcm.42.11.5302-5308.2004

  132. 132.

    Kusters J.G., van Vliet A.H., Kuipers E.J. Pathogenesis of Helicobacter pylori infection. Clin. Microbiol. Rev. 2006;19:449-490.

    Not in our library10.1128/cmr.00054-05

  133. 133.
    A Global Overview of the Genetic and Functional Diversity in the Helicobacter pylori cag Pathogenicity Island · 2010
    Corrected
  134. 134.

    Markovska R., Boyanova L., Yordanov D., Stankova P., Gergova G., Mitov I. Status of Helicobacter pylori cag pathogenicity island (cagPAI) integrity and significance of its individual genes. Infect. Genet. Evol. 2018;59:167-171.

    Not in our library10.1016/j.meegid.2018.02.009

  135. 135.

    Yao Y., Shen Y., Zhu L., Ni Y., Wang H., Shao S. Preliminary study and bioinformatics analysis on the potential role of CagQ in type IV secretion system of H. pylori. Microb. Pathog. 2018;116:1-7.

    Not in our library10.1016/j.micpath.2017.12.076

  136. 136.
    An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA · 2012
    Not checked
  137. 137.

    Saha A., Backert S., Hammond C.E., Gooz M., Smolka A.J. Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology. 2010;139:239-248.

    Not in our library10.1053/j.gastro.2010.03.036

  138. 138.

    Tegtmeyer N., Hartig R., Delahay R.M., Rohde M., Brandt S., Conradi J., Takahashi S., Smolka A.J., Sewald N., Backert S. A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J. Biol. Chem. 2010;285:23515-23526.

    Not in our library10.1074/jbc.m109.096214

  139. 139.

    Román Roman A., Martínez Santos V.I., Castañón Sánchez C.A., Albañil Muñoz A.J., Mendoza P.G., Soto Flores D.G., Martínez Carrillo D.N., Tilapa G.F. CagL polymorphisms D58/K59 are predominant in Helicobacter pylori strains isolated from Mexican patients with chronic gastritis. Gut Pathog. 2019;11:5.

    Not in our library10.1186/s13099-019-0286-9

  140. 140.

    Yadegar A., Mohabati Mobarez A., Zali M.R. Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases. Cancer Med. 2019;8:1619-1632.

    Not in our library10.1002/cam4.1941

  141. 141.
    Preservation of Helicobacter pylori CagA Translocation and Host Cell Proinflammatory Responses in the Face of CagL Hypervariability at Amino Acid Residues 58/59. · 2015
    Not checked
  142. 142.

    Gorrell R.J., Zwickel N., Reynolds J., Bulach D., Kwok T. Helicobacter pylori CagL hypervariable motif: A global analysis of geographical diversity and association with gastric cancer. J. Infect. Dis. 2016;213:1927-1931.

    Not in our library10.1093/infdis/jiw060

  143. 143.

    Covacci A., Rappuoli R. Tyrosine phosphorylated bacterial proteins: Trojan horses for the host cell. J. Exp. Med. 2000;191:587-592.

    Not in our library10.1084/jem.191.4.587

  144. 144.
    Helicobacter pylori Exploits a Unique Repertoire of Type IV Secretion System Components for Pilus Assembly at the Bacteria-Host Cell Interface · 2011
    No notice
  145. 145.

    Viala J., Chaput C., Boneca I.G., Cardona A., Girardin S.E., Moran A.P., Athman R., Memet S., Huerre M.R., Coyle A.J., et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat. Immunol. 2004;5:1166-1174.

    Not in our library10.1038/ni1131

  146. 146.

    Varga M.G., Shaffer C.L., Sierra J.C., Suarez G., Piazuelo M.B., Whitaker M.E., Romero-Gallo J., Krishna U.S., Delgado A., Gomez M.A., et al. Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene. 2016;35:6262-6269.

    Not in our library10.1038/onc.2016.158

  147. 147.
    Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis · 2017
    No notice
  148. 148.

    Zhou P., She Y., Dong N., Li P., He H., Borio A., Wu Q., Lu S., Ding X., Cao Y., et al. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP heptose. Nature. 2018;561:122-126.

    Not in our library10.1038/s41586-018-0433-3

  149. 149.

    Jiménez-Soto L.F., Haas R. The CagA toxin of Helicobacter pylori: Abundant production but relatively low amount translocated. Sci. Rep. 2016;6:23227.

    Not in our library10.1038/srep23227

  150. 150.

    Clague M.J., Urbé S. Ubiquitin: Same molecule, different degradation pathways. Cell. 2010;143:682-685.

    Not in our library10.1016/j.cell.2010.11.012

  151. 151.

    Abdullah M., Greenfeld L.K., Bronte-Tinkew D., Capurro M.I., Rizzuti D., Jones N.L. VacA promotes CagA accumulation in gastric epithelial cells during Helicobacter pylori infection. Sci. Rep. 2019;9:38.

    Not in our library10.1038/s41598-018-37095-4

  152. 152.

    Tohidpour A. CagA-mediated pathogenesis of Helicobacter pylori. Microb. Pathog. 2016;93:44-55.

    Not in our library10.1016/j.micpath.2016.01.005

  153. 153.

    Zanotti G., Cendron L. Structural and functional aspects of the Helicobacter pylori secretome. World J. Gastroenterol. 2014;20:1402-1423.

    Not in our library10.3748/wjg.v20.i6.1402

  154. 154.

    Mimuro H., Suzuki T., Tanaka J., Asahi M., Haas R., Sasakawa C. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol. Cell. 2002;10:745-755.

    Not in our library10.1016/s1097-2765(02)00681-0

  155. 155.

    Saito Y., Murata-Kamiya N., Hirayama T., Ohba Y., Hatakeyama M. Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21. J. Exp. Med. 2010;207:2157-2174.

    Not in our library10.1084/jem.20100602

  156. 156.

    Li N., Feng Y., Hu Y., He C., Xie C., Ouyang Y., Artim S.C., Huang D., Zhu Y., Luo Z., et al. Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway. J. Exp. Clin. Cancer Res. 2018;37:280.

    Not in our library10.1186/s13046-018-0962-5

  157. 157.

    Higashi H., Tsutsumi R., Fujita A., Yamazaki S., Asaka M., Azuma T., Hatakeyama M. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc. Natl. Acad. Sci. USA. 2002;99:14428-14433.

    Not in our library10.1073/pnas.222375399

  158. 158.

    Li Q., Liu J., Gong Y., Yuan Y. Association of CagA EPIYA-D or EPIYA-C phosphorylation sites with peptic ulcer and gastric cancer risks: A meta-analysis. Medicine. 2017;96:e6620.

    Not in our library10.1097/md.0000000000006620

  159. 159.

    Zhang X.S., Tegtmeyer N., Traube L., Jindal S., Perez-Perez G., Sticht H., Backert S., Blaser M.J. A specific A/T polymorphism in Western tyrosine phosphorylation B-motifs regulates Helicobacter pylori CagA epithelial cell interactions. PLoS Pathog. 2015;11:e1004621.

    Not in our library10.1371/journal.ppat.1004621

  160. 160.

    Choi S.I., Yoon C., Park M.R., Lee D., Kook M.C., Lin J.X., Kang J.H., Ashktorab H., Smoot D.T., Yoon S.S., et al. CDX1 expression induced by CagA-expressing Helicobacter pylori promotes gastric tumorigenesis. Mol. Cancer Res. 2019;17:2169-2183.

    Not in our library10.1158/1541-7786.mcr-19-0181

  161. 161.
    Cdx1 and Cdx2 exhibit transcriptional specificity in the intestine. · 2013
    Not checked
  162. 162.

    Wroblewski L.E., Choi E., Petersen C., Delgado A.G., Piazuelo M.B., Romero-Gallo J., Lantz T.L., Zavros Y., Coffey R.J., Goldenring J.R., et al. Targeted mobilization of Lrig1+ gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system. Proc. Nat. Acad. Sci. USA. 2019;116:19652-19658.

    Not in our library10.1073/pnas.1903798116

  163. 163.

    Tsugawa H., Suzuki H., Saya H., Hatakeyama M., Hirayama T., Hirata K., Nagano O., Matsuzaki J., Hibi T. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe. 2012;12:764-777.

    Not in our library10.1016/j.chom.2012.10.014

  164. 164.

    Terebiznik M.R., Raju D., Vázquez C.L., Torbricki K., Kulkarni R., Blanke S.R., Yoshimori T., Colombo M.I., Jones N.L. Efect of Helicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy. 2009;5:370-379.

    Not in our library10.4161/auto.5.3.7663

  165. 165.

    Ricci V. Relationship between VacA toxin and host cell autophagy in Helicobacter pylori infection of the human stomach: A few answers, many questions. Toxins. 2016;8:203.

    Not in our library10.3390/toxins8070203

  166. 166.

    Atherton J.C., Cao P., Peek R.M., Tummuru M.K., Blaser M.J., Cover T.L. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori association of specific VacA types with cytotoxin production and peptic ulceration. J. Biol. Chem. 1995;270:17771-17777.

    Not in our library10.1074/jbc.270.30.17771

  167. 167.

    Rhead J.L., Letley D.P., Mohammadi M., Hussein N., Mohagheghi M.A., Eshagh Hosseini M., Atherton J.C. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133:926-936.

    Not in our library10.1053/j.gastro.2007.06.056

  168. 168.

    Bridge D.R., Merrell D.S. Polymorphism in the Helicobacter pylori CagA and VacA toxins and disease. Gut Microbes. 2003;4:101-117.

    Not in our library10.4161/gmic.23797

  169. 169.

    Chung C., Olivares A., Torres E., Yilmaz O., Cohen H., Perez-Perez G. Diversity of VacA intermediate region among Helicobacter pylori strains from several regions of the world. J. Clin. Microbiol. 2010;48:690-696.

    Not in our library10.1128/jcm.01815-09

  170. 170.

    McClain M.S., Cao P., Iwamoto H., Vinion-Dubiel A.D., Szabo G., Shao Z., Cover T.L. A 12 amino acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. J. Bacteriol. 2001;183:6499-6508.

    Not in our library10.1128/jb.183.22.6499-6508.2001

  171. 171.

    Trang T.T.H., Binh T.T., Yamaoka Y. Relationship between vacA Types and Development of Gastroduodenal Diseases. Toxins. 2016;8:182.

    Not in our library10.3390/toxins8060182

  172. 172.

    Atherton J.C., Sharp P.M., Cover T.L., Gonzalez-Valencia G., Peek R.M., Thompson S.A., Hawkey C.J., Blaser M.J. Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori comprise two geographically widespread types, m1 and m2, and have evolved through limited recombination. Curr. Microbiol. 1999;39:211-218.

    Not in our library10.1007/s002849900447

  173. 173.

    Forsyth M.H., Atherton J.C., Blaser M.J., Cover T.L. Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect. Immun. 1998;66:e3088-e3094.

    Not in our library10.1128/iai.66.7.3088-3094.1998

  174. 174.

    Matos J.I., de Sousa H.A., Marcos-Pinto R., Dinis-Ribeiro M. Helicobacter pylori CagA and VacA genotypes and gastric phenotype: A meta-analysis. Eur. J. Gastroenterol. Hepatol. 2013;25:1431-1441.

    Not in our library10.1097/meg.0b013e328364b53e

  175. 175.

    Liu X., He B., Cho W.C., Pan Y., Chen J., Ying H., Wang F., Lin K., Peng H., Wang S. A systematic review on the association between the Helicobacter pylori vacA i genotype and gastric disease. FEBS Open Bio. 2016;6:409-417.

    Not in our library10.1002/2211-5463.12046

  176. 176.

    Sezikli M., Guliter S., Apan T.Z., Aksoy A., Keles H., Ozkurt Z.N. Frequencies of serum antibodies to Helicobacter pylori CagA and VacA in a Turkish population with various gastroduodenal diseases. Int. J. Clin. Pract. 2006;60:1239-1243.

    Not in our library10.1111/j.1742-1241.2005.00778.x

  177. 177.

    Li Q., Liu J., Gong Y., Yuan Y. Serum VacA antibody is associated with risks of peptic ulcer and gastric cancer: A meta-analysis. Microb. Pathog. 2016;99:220-228.

    Not in our library10.1016/j.micpath.2016.08.030

  178. 178.

    Butt J., Varga M.G., Blot W.J., Teras L., Visvanathan K., Le Marchand L., Haiman C., Chen Y., Bao Y., Sesso H.D., et al. Serologic response to Helicobacter pylori proteins associated with risk of colorectal cancer among diverse populations in the United States. Gastroenterology. 2019;156:175-186.

    Not in our library10.1053/j.gastro.2018.09.054

  179. 179.

    Ji X., Fernandez T., Burroni D., Pagliaccia C., Atherton J.C., Reyrat J.M., Rappuoli R., Telford J.L. Cell specificity of Helicobacter pylori cytotoxin is determined by a short region in the polymorphic midregion. Infect. Immun. 2000;68:3754-3757.

    Not in our library10.1128/iai.68.6.3754-3757.2000

  180. 180.

    Wang W.-C., Wang H.-J., Kuo C.-H. Two distinctive cell binding patterns by vacuolating toxin fused with glutathione S transferase: One high affinity m1 specific binding and the other lower affinity binding for variant m forms. Biochemistry. 2001;40:11887-11896.

    Not in our library10.1021/bi010065u

  181. 181.

    Terebiznik M.R., Vazquez C.L., Torbicki K., Banks D., Wang T., Hong W., Blanke S.R., Colombo M.I., Jones N.L. Helicobacter pylori VacA Toxin Promotes Bacterial Intracellular Survival in Gastric Epithelial Cells. Infect. Immun. 2006;74:6599-6614.

    Not in our library10.1128/iai.01085-06

  182. 182.

    Capurro M.I., Greenfield L.K., Prashar A., Xia S., Abdullah M., Wong H., Zhong X.Z., Bertaux-Skeirik N., Chakrabarti J., Siddiqui I., et al. VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1. Nat. Microbiol. 2019;4:1411-1423.

    Not in our library10.1038/s41564-019-0441-6

  183. 183.

    Clausen T., Southan C., Ehrmann M. The HtrA family of proteases: Implications for protein composition and cell fate. Mol. Cell. 2002;10:443-455.

    Not in our library10.1016/s1097-2765(02)00658-5

  184. 184.

    Clausen T., Kaiser M., Huber R., Ehrmann M. HTRA proteases: Regulated proteolysis in protein quality control. Nat. Rev. Mol. Cell Biol. 2011;12:152-162.

    Not in our library10.1038/nrm3065

  185. 185.

    Page M.J., Di Cera E. Evolution of peptidase diversity. J. Biol. Chem. 2008;283:30010-30014.

    Not in our library10.1074/jbc.m804650200

  186. 186.

    Merdanovic M., Clausen T., Kaiser M., Huber R., Ehrmann M. Protein quality control in the bacterial periplasm. Annu. Rev. Microbiol. 2011;65:149-168.

    Not in our library10.1146/annurev-micro-090110-102925

  187. 187.

    Gottesman S., Wickner S., Maurizi M.R. Protein quality control: Triage by chaperone and proteases. Genes Dev. 1997;11:815-823.

    Not in our library10.1101/gad.11.7.815

  188. 188.

    Ingmer H., Brøndsted L. Proteases in bacterial pathogenesis. Res. Microbiol. 2009;160:704-710.

    Not in our library10.1016/j.resmic.2009.08.017

  189. 189.

    Frees D., Brøndsted L., Ingmer H. Bacterial proteases and virulence. Subcell. Biochem. 2013;66:161-192.

    Not in our library10.1007/978-94-007-5940-4_7

  190. 190.

    Skórko-Glonek J., Figaj D., Zarzecka U., Przepiora T., Renke J., Lipinska B. The extracellular bacterial HtrA proteins as potential therapeutic targets and vaccine candidates. Curr. Med. Chem. 2017;24:2174-2204.

    Not in our library10.2174/0929867323666161223145825

  191. 191.

    Zarzecka U., Modrak-Wójcik A., Figaj D., Apanowicz M., Lesner A., Bzowska A., Lipinska B., Zawilak-Pawlik A., Backert S., Skorko-Glonek J. Properties of the HtrA Protease from Bacterium Helicobacter pylori Whose Activity Is Indispensable for Growth Under Stress Conditions. Front. Microbiol. 2019;10:961.

    Not in our library10.3389/fmicb.2019.00961

  192. 192.

    Hoy B., Brandstetter H., Wessler S. The stability and activity of recombinant Helicobacter pylori HtrA under stress conditions. J. Basic Microbiol. 2013;53:402-409.

    Not in our library10.1002/jobm.201200074

  193. 193.

    Harrer A., Boehm M., Backert S., Tegtmeyer N. Overexpression of serine protease HtrA enhances disruption of adherens junctions, paracellular transmigration and type IV secretion of CagA by Helicobacter pylori. Gut Pathog. 2017;9:40.

    Not in our library10.1186/s13099-017-0189-6

  194. 194.

    Van der Pol E., Boing A.N., Harrison P., Sturk A., Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 2012;64:676-705.

    Not in our library10.1124/pr.112.005983

  195. 195.

    Kim J.H., Lee J., Park J., Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles. Semin. Cell Dev. Biol. 2015;40:97-104.

    Not in our library10.1016/j.semcdb.2015.02.006

  196. 196.

    Deatherage B.L., Lara J.C., Bergsbaken T., Rassoulian Barrets S.L., Lara S., Cookson B.T. Biogenesis of bacterial outer membrane vesicles. Mol. Microbiol. 2009;72:1395-1407.

    Not in our library10.1111/j.1365-2958.2009.06731.x

  197. 197.
    Biochemical and functional characterization of Helicobacter pylori vesicles · 2010
    No notice
  198. 198.

    Unal C.M., Schaar V., Riesbeck K. Bacterial outer membrane vesicles in disease and preventive medicine. Semin. Immunopathol. 2011;33:395-408.

    Not in our library10.1007/s00281-010-0231-y

  199. 199.

    Fiocca R., Necchi V., Sommi P., Ricci V., Telford J., Cover T.L., Solcia E. Release of Helicobacter pylori vacuolating cytotoxin by both a specific secretion pathway and budding of outer membrane vesicles. Uptake of released toxin and vesicles by gastric epithelium. J. Pathol. 1999;188:220-226.

    Not in our library10.1002/(sici)1096-9896(199906)188:2<220::aid-path307>3.0.co;2-c

  200. 200.

    Keenan J., Day T., Neal S., Cook B., Perez-Perez G., Allardyce R., Bagshaw P. A role for the bacterial outer membrane in the pathogenesis of Helicobacter pylori infection. FEMS Microbiol. Lett. 2000;182:259-264.

    Not in our library10.1111/j.1574-6968.2000.tb08905.x

  201. 201.

    Mullaney E., Brown P.A., Smith S.M., Botting C.H., Yamaoka Y.Y., Terres A.M., Kelleher D.P., Windle H.J. Proteomic and functional characterization of the outer membrane vesicles from the gastric pathogen Helicobacter pylori. Proteom. Clin. Appl. 2009;3:785-796.

    Not in our library10.1002/prca.200800192

  202. 202.

    Olofsson A., Skalman L.N., Obi I., Lundmark R., Arnqvist A. Uptake of Helicobacter pylori Vesicles Is Facilitated by Clathrin Dependent and Clathrin-Independent Endocytic Pathways. mBio. 2014;5:e00979-14.

    Not in our library10.1128/mbio.00979-14

  203. 203.

    Parker H., Keenan J.I. Composition and function of Helicobacter pylori outer membrane vesicles. Microbes Infect. 2012;14:9-16.

    Not in our library10.1016/j.micinf.2011.08.007

  204. 204.

    Ellis T.N., Kuehn M.J. Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol. Mol. Biol. Rev. 2010;74:81-94.

    Not in our library10.1128/mmbr.00031-09

  205. 205.

    Winter J.L.D., Rhead J., Atherton J., Robinson K. Helicobacter pylori membrane vesicles stimulate innate pro- and anti-inflammatory responses and induce apoptosis in Jurkat T cells. Infect. Immun. 2014;82:1372-1381.

    Not in our library10.1128/iai.01443-13

  206. 206.

    Choi H.I., Choi J.P., Seo J., Kim B.J., Rho M., Han J.K., Kim J.G. Helicobacter pylori-derived extracellular vesicles increased in the gastric juices of gastric adenocarcinoma patients and induced inflammation mainly via specific targeting of gastrin epithelial cells. Exp. Mol. Med. 2017;49:e330.

    Not in our library10.1038/emm.2017.47

  207. 207.

    Chitcholtan K., Hampton M.B., Keenan J.I. Outer membrane vesicles enhance the carcinogenic potential of Helicobacter pylori. Carcinogenesis. 2008;29:2400-2405.

    Not in our library10.1093/carcin/bgn218

  208. 208.

    Hanigan M.H. gamma-Glutamyl transpeptidase, a glutathionase: Its expression and function in carcinogenesis. Chem. Biol. Interact. 1998;111:333-342.

    Not in our library10.1016/s0009-2797(97)00170-1

  209. 209.

    Chevalier C., Thiberge J.M., Ferrero R., Labigne A. Essential role of Helicobacter pylori g-glutamyltranspeptidase for the colonization of the gastric mucosa of mice. Mol. Microbiol. 1999;31:1359-1372.

    Not in our library10.1046/j.1365-2958.1999.01271.x

  210. 210.

    Mcgovern K.J., Blanchard T.G., Gutierrez J.A., Czinn S.J., Krakowka S., Youngman P. g-glutamyltransferase is a Helicobacter pylori virulence factor but is not essential for colonization. Infect. Immun. 2001;69:4168-4173.

    Not in our library10.1128/iai.69.6.4168-4173.2001

  211. 211.

    Wüstner S., Anderl F., Wanisch A., Sachs C., Steiger K., Nerlich A., Vieth M., Mejías-Luque R., Gerhard M. Helicobacter pylori γ-glutamyl transferase contributes to colonization and diferential recruitment of T cells during persistence. Sci. Rep. 2017;7:13636.

    Not in our library10.1038/s41598-017-14028-1

  212. 212.

    Bravo J., Díaz P., Corvalán A.H., Quest A.F.G. A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells. Cancers. 2019;11:801.

    Not in our library10.3390/cancers11060801

  213. 213.

    Kim K.M., Lee S.G., Kim J.M., Kim D.S., Song J.Y., Kang H.L., Lee W.K., Cho M.J., Rhee K.H., Youn H.S., et al. Helicobacter pylori γ-glutamyltranspeptidase induces cell cycle arrest at the G1-S phase transition. J. Microbiol. 2010;48:372-377.

    Not in our library10.1007/s12275-010-9293-8

  214. 214.

    Gong M., Ling S.S.M., Lui S.Y., Yeoh K.G., Ho B. Helicobacter pylori γ-glutamyl transpeptidase is a pathogenic factor in the development of peptic ulcer disease. Gastroenterology. 2010;139:564-573.

    Not in our library10.1053/j.gastro.2010.03.050

  215. 215.

    Rimbara E., Mori S., Kim H., Shibayama K. Role of γ-glutamyltranspeptidase in the pathogenesis of Helicobacter pylori infection. Microbiol. Immunol. 2013;57:665-673.

    Not in our library10.1111/1348-0421.12089

  216. 216.

    Capitani N., Codolo G., Vallese F., Minervini G., Grassi A., Cianchi F., Troilo A., Fischer W., Zanotti G., Baldari C.T., et al. The lipoprotein HP1454 of Helicobacter pylori regulates T-cell response by shaping T-cell receptor signalling. Cell. Microbiol. 2019;21:e13006.

    Not in our library10.1111/cmi.13006

  217. 217.

    Waskito L.A., Miftahussurur M., Lusida M.I., Syam A.F., Suzuki R., Subsomwong P., Uchida T., Hamdan M., Nasronudin, Yamaoka Y. Distribution and clinical associations of integrating conjugative elements and cag pathogenicity islands of Helicobacter pylori in Indonesia. Sci. Rep. 2018;8:6073.

    Not in our library10.1038/s41598-018-24406-y

  218. 218.

    Morey P., Pfannkuch L., Pang E., Boccellato F., Sigal M., Imai-Matsushima A., Dyer V., Koch M., Mollenkopf H.J., Schlaermann P., et al. Helicobacter pylori depletes cholesterol in gastric glands to prevent interferon gamma signaling and escape the inflammatory response. Gastroenterology. 2018;154:1391-1404.

    Not in our library10.1053/j.gastro.2017.12.008

  219. 219.

    Jiang F., Wu Z., Zheng Y., Frana T.S., Sahin O., Zhang Q., Li G. Genotypes and antimicrobial susceptibility profiles of hemolytic Escherichia coli from diarrheic piglets. Foodborne Pathog. Dis. 2019;16:94-103.

    Not in our library10.1089/fpd.2018.2480

  220. 220.

    Ellington M.J., Ekelund O., Aarestrup F.M., Canton R., Doumith M., Giske C., Grundman H., Hasman H., Holden M.T.G., Hopkins K.L., et al. The role of whole genome sequencing in antimicrobial susceptibility testing of bacteria: Report from the EUCAST Subcommittee. Clin. Microbiol. Infect. 2017;23:2-22.

    Not in our library10.1016/j.cmi.2016.11.012

  221. 221.
    Rapid, comprehensive, and affordable mycobacterial diagnosis with whole-genome sequencing: a prospective study · 2016
    No notice
  222. 222.

    Witney A.A., Cosgrove C.A., Arnold A., Hinds J., Stoker N.G., Butcher P.D. Clinical use of whole genome sequencing for Mycobacterium tuberculosis. BMC Med. 2016;14:46.

    Not in our library10.1186/s12916-016-0598-2

  223. 223.
    Whole-Genome Sequencing-Based Characterization of 100 <named-content content-type="genus-species">Listeria monocytogenes</named-content> Isolates Collected from Food Processing Environments over a Four-Year Period · 2019
    Not checked
  224. 224.
    Whole Genome Sequencing-Based Comparison of Food Isolates of Cronobacter sakazakii · 2019
    Not checked
  225. 225.
    Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study · 2015
    Corrected
  226. 226.

    Metzker M.L. Sequencing technologies-the next generation. Nat. Rev. Genet. 2010;11:31-46.

    Not in our library10.1038/nrg2626

  227. 227.

    Mardis E.R. Next-generation DNA sequencing methods. Annu. Rev. Genom. Hum. Genet. 2008;9:387-402.

    Not in our library10.1146/annurev.genom.9.081307.164359

  228. 228.

    Edwards M.S., McLaughlin R.W., Li J., Wan X.-L., Liu Y., Xie H.-X., Hao Y.-J., Zheng J.-S. Putative virulence factors of Plesiomonas shigelloides. Antonie Van Leeuwenhoek. 2019;1-12.

    Not in our library10.1007/s10482-019-01303-6

  229. 229.

    Lauener F.N., Imkamp F., Lehours P., Buissonnière A., Benejat L., Zbinden R., Keller P.M., Wagner K. Genetic Determinants and Prediction of Antibiotic Resistance Phenotypes in Helicobacter pylori. J. Clin. Med. 2019;8:53.

    Not in our library10.3390/jcm8010053

  230. 230.

    Tuan V.P., Narith D., Tshibangu-Kabamba E., Dung H.D.Q., Viet P.T., Sokomoth S., Binh T.T., Sokhem S., Tri T.D., Ngov S., et al. A Next-Generation Sequencing-Based Approach to Identify Genetic Determinants of Antibiotic Resistance in Cambodian Helicobacter pylori Clinical Isolates. J. Clin. Med. 2019;8:858.

    Not in our library10.3390/jcm8060858

  231. 231.

    Chen J., Ye L., Jin L., Xu X., Xu P., Wang X., Li H. Application of next-generation sequencing to characterize novel mutations in clarithromycin-susceptible Helicobacter pylori strains with A2143G of 23S rRNA gene. Ann. Clin. Microbiol. Antimicrob. 2018;17:10.

    Not in our library10.1186/s12941-018-0259-8

  232. 232.

    Imkamp F., Lauener F.N., Pohl D., Lehours P., Vale F.F., Jehanne Q., Zbinden R., Keller P.M., Wagner K. Rapid Characterization of Virulence Determinants in Helicobacter pylori Isolated from Non-Atrophic Gastritis Patients by Next-Generation Sequencing. J. Clin. Med. 2019;8:1030.

    Not in our library10.3390/jcm8071030

  233. 233.

    Gerrits M.M., van Vliet A.H., Kuipers E.J., Kusters J.G. Helicobacter pylori and antimicrobial resistance: Molecular mechanisms and clinical implications. Lancet Infect. Dis. 2006;6:699-709.

    Not in our library10.1016/s1473-3099(06)70627-2

  234. 234.

    Ogawa H., Iwamoto A., Tanahashi T., Okada R., Yamamoto K., Nishiumi S., Yoshida M., Azuma T. Genetic variants of Helicobacter pylori type IV secretion system components CagL and CagI and their association with clinical outcomes. Gut Pathog. 2017;9:21.

    Not in our library10.1186/s13099-017-0165-1

  235. 235.

    Burton P.R., Clayton D.G., Cardon L.R., Craddock N., Deloukas P., Duncanson A., Kwiatkowski D.P., McCarthy M.I., Ouwehand W.H., Samani N.J., et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661-678.

    Not in our library10.1038/nature05911

  236. 236.

    Berthenet E., Yahara K., Thorell K., Pascoe B., Meric G., Mikhail J.M., Engstrand L., Enroth H., Burette A., Megraud F., et al. A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk. BMC Biol. 2018;16:84.

    Not in our library10.1186/s12915-018-0550-3

  237. 237.

    Maldonado-Contreras A., Goldfarb K.C., Godoy-Vitorino F., Karaoz U., Contreras M., Blaser M.J., Brodie E.L., Dominguez-Bello M.G. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J. 2011;5:574-579.

    Not in our library10.1038/ismej.2010.149

  238. 238.

    Jo H.J., Kim J., Kim N., Park J.H., Nam R.H., Seok Y.J., Kim Y.R., Kim J.S., Kim J.M., Kim J.M., et al. Analysis of gastric microbiota by pyrosequencing: Minor role of bacteria other than Helicobacter pylori in the gastric carcinogenesis. Helicobacter. 2016;21:364-374.

    Not in our library10.1111/hel.12293

  239. 239.

    Schulz C., Schütte K., Koch N., Vilchez-Vargas R., Wos-Oxley M.L., Oxley A.P.A., Vital M., Malfertheiner P., Pieper D.H. The active bacterial assemblages of the upper GI tract in individuals with and without Helicobacter infection. Gut. 2018;67:216-225.

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    Garrett W.S. Cancer and the microbiota. Science. 2015;348:80-86.

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    Wang L., Zhou J., Xin Y., Geng C., Tian Z., Yu X., Dong Q. Bacterial overgrowth and diversification of microbiota in gastric cancer. Eur. J. Gastroenterol. Hepatol. 2016;28:261-266.

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    Different gastric microbiota compositions in two human populations with high and low gastric cancer risk in Colombia · 2016
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    Association Between Gut Microbiota and Helicobacter pylori-Related Gastric Lesions in a High-Risk Population of Gastric Cancer · 2018
    No notice

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