Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 21, 2026.

Influenza virus activation of the interferon system

Marian J. Killip, Ervin Fodor, Richard E. Randall

Virus Research · 2015 · Review · CC BY

doi:10.1016/j.virusres.2015.02.003

Abstract

The host interferon (IFN) response represents one of the first barriers that influenza viruses must surmount in order to establish an infection. Many advances have been made in recent years in understanding the interactions between influenza viruses and the interferon system. In this review, we summarise recent work regarding activation of the type I IFN response by influenza viruses, including attempts to identify the viral RNA responsible for IFN induction, the stage of the virus life cycle at which it is generated and the role of defective viruses in this process.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The influenza viruses are a leading cause of respiratory illness in humans and are responsible for annual seasonal outbreaks that have serious economic impact. In addition, the wide host range of the virus and the potential for genome reassortment between human influenza viruses and those of other species mean these viruses present a pandemic threat. To establish a productive infection and thus cause disease, influenza viruses must overcome host innate immune responses that are very rapidly activated during infections. The interferon (IFN) family of antiviral cytokines play a major role in these responses and are critical in restricting the early stages of virus infections prior to the activation of the adaptive immune system. The IFNs and other innate immune mediators have serious implications for the outcome of influenza virus infections in terms of disease severity, since highly pathogenic viruses are often associated with excessive cytokine responses. In this review, we summarise recent developments in our understanding of how influenza viruses activate the IFN system and highlight areas in which this understanding is still incomplete.

The interferon response to influenza virus

The IFNs are expressed and secreted following the detection of viral components within infected cells; subsequent binding of IFN to its cognate receptor at cell surfaces leads to the upregulation of hundreds of different interferon-stimulated genes (ISGs) that establish an ‘antiviral state’ to efficiently limit further replication and spread of the virus (reviewed in ). Of these ISGs, several have been identified as having direct anti-influenza virus activity. These include the Mx family of GTPases, which are thought to form oligomeric rings around viral nucleocapsids to inhibit their nuclear import and/or replication; viperin, which affects virus budding and thus limits the release of viral particles from infected cells (although the contribution of viperin to the restriction of influenza virus replication in vivo is less clear-cut, ); and the IFN-induced transmembrane (IFITM) family members (in particular IFITM3), which interfere with fusion between viral and endosomal membranes thereby limiting viral entry.

The IFNs are classified into three types according to their amino acid sequence and the type of receptor through which they signal. The type I IFNs (which include multiple IFN-α subtypes and IFN-β) and the type III IFNs (IFN-λ) are directly upregulated following virus infection; these are the major IFNs secreted following influenza virus infections in vitro and in vivo. In contrast, type II IFN (IFN-γ) is secreted by activated T lymphocytes and NK cells and will not be discussed further in this review. Airway epithelial cells, plasmacytoid dendritic cells (pDCs) and macrophages are the main producers of IFN during influenza virus infections. Several studies suggest that airway epithelial cells are primarily responsible for type III IFN production while dendritic cells and alveolar macrophages are the major source of type I IFNs. The induction of both type I and type III IFNs in virus-infected epithelial cells is thought to occur in response to the same viral ligands and via the same signalling components; furthermore, the panel of ISGs upregulated in airway epithelia in response to type I and type III IFNs following influenza virus infection shows complete overlap. However, while the type I IFN receptor is expressed at the surface of all cells, expression of the type III IFN receptor is primarily restricted to epithelial cells in the respiratory and gastrointestinal tracts. During an influenza virus infection, it is possible that this differential expression of the type III IFN receptor functions to elicit an antiviral response in airway epithelia while restricting the activation of immune cells and associated lung pathology.

The IFN induction cascade becomes stimulated following the recognition of certain molecular structures that are absent in uninfected cells, termed pathogen-associated molecular patterns (PAMPs). For RNA virus infections, these PAMPs are predominantly certain features of viral RNA that are not usually present in cellular RNAs, such as regions of double-stranded RNA (dsRNA) or the presence of a 5′-triphosphate (5′ppp) or a 5′-diphosphate (5′pp) group. The pathogen-recognition receptors (PRRs) play a critical role in the distinction of self from non-self molecules by binding to PAMPs within infected cells. Two types of PRRs have been implicated in the induction of IFNs by influenza viruses, with the role of a particular PRR depending on the cell type and nature of the viral stimuli. The Toll-like receptor (TLR) family of transmembrane proteins are able to recognise a wide range of microbial ligands, and signal downstream through either MyD88 (myeloid differentiation primary response 88) or TRIF (Toll-interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon (IFN)-β) adaptor proteins to stimulate IFN expression, depending on the particular TLR (reviewed in ). TLR7 is a receptor for ssRNA and recognises incoming virions in endosomal compartments during influenza virus infection of pDCs; it is consequently required for the production of high levels of type I IFNs by these cells. In other cell types, TLR7 is dispensable for IFN induction by RNA viruses including influenza virus, either because it is not expressed or because its localisation is non-endosomal. TLR3 recognises dsRNA and is also activated by influenza virus infection. However, although TLR3 contributes to IFN induction by other viruses (reviewed in ), TLR3-deficient airway epithelial cells and pDCs have normal type I IFN responses to influenza virus infection; instead, TLR3 in the context of influenza virus infections functions to activate pro-inflammatory signalling pathways.

Non-self RNAs in the cytoplasm are detected by a second group of PRRs, the cytosolic RIG-I-like receptors (RLRs), consisting of RIG-I, MDA-5 and LGP2. These receptors are essential for IFN induction during RNA virus infections of non-pDC cell-types, and mice that are deficient in RLR signalling pathways are extremely susceptible to RNA viruses despite possessing intact TLR systems. Both RIG-I and MDA-5 contain two caspase activation and recruitment domains (CARDs) at their N-terminus, an RNA helicase domain possessing dsRNA-dependent ATPase activity and a C-terminal regulatory domain (CTD). Ligand binding to the CTD and the helicase domain induces a conformational change in the RLRs that exposes the CARDs. Activity following ligand binding is modulated by the posttranslational modification of the CARDs by dephosphorylation and/or ubiquitination (reviewed in ). For example, TRIM25, RIPLET and/or MEX3C-dependent Lys63-linked ubiquitination of the CARDs occurs following ligand binding to RIG-I. Additionally, free Lys63 polyubiquitin chains have been reported to bind RIG-I and MDA-5 CARDs and stimulate activity. Downstream signal transduction occurs by the CARD-dependent association of RIG-I/MDA-5 with the mitochondrial antiviral signalling protein (MAVS) at the outer mitochondrial membrane. This interaction promotes MAVS oligomerisation and the assembly of large multiprotein complexes that activate NF-κB and the IFN regulatory factors (IRF3 or IRF7, depending on the IFN subtype, ) to stimulate expression of type I and type III IFNs. LGP2 has a similar structure to RIG-I and MDA-5 but lacks the CARDs; this protein has thus been implicated in the regulation of RIG-I and MDA-5 activity.

RIG-I and MDA-5 each recognise different types of viral RNA, with RIG-I most efficiently activated by short stretches of 5′ppp or 5′pp dsRNA while MDA-5 is activated by longer stretches of dsRNA in a 5′ phosphate-independent manner; these PRRs have therefore been shown to recognise different families of RNA viruses. Knockdown studies have shown that IFN induction in response to influenza virus infection is predominantly mediated through RIG-I, and influenza virus-induced IFN expression in airway epithelial cells, the primary site of influenza virus replication, is RIG-I-dependent. MDA-5 may still contribute to IFN induction by influenza viruses however, since small reductions in IFN induction and ISG responses can be seen in infected MDA-5-deficient cells compared to control cells. Moreover, type I IFNs are still produced following influenza virus infection or transfections of influenza RNA in chicken cells, which lack RIG-I. Instead, IFN induction in this system is mediated through MDA-5.

Influenza virus replication

The influenza virus genome is composed of eight different segments of single-stranded negative-sense viral RNA (vRNA) that exists in virions in the form of viral ribonucleoproteins (vRNPs) which are the minimum units required for viral transcription and replication. vRNPs are held in a closed circular conformation by the binding of the trimeric viral RNA-dependent RNA polymerase to the partially complementary 5′ and 3′ termini of the vRNA, with the remainder of the vRNA segment bound along its length by viral nucleoprotein (NP) oligomers (reviewed in ). Following binding of virions to sialic acid-containing receptors on the surface of host cells, virus particles are taken into the cell by endocytosis followed by vRNP release into the cytoplasm and import to the nucleus, where they serve as the templates for viral transcription and replication. vRNPs are first transcribed by the vRNP-associated polymerase in a reaction primed by 5′ capped 10–13nt RNAs that are derived from cellular pre-mRNAs through the polymerase cap-binding and endonucleolytic activities (reviewed in ). Viral mRNA synthesis is therefore dependent on the activity of host RNA polymerase II and can thus be inhibited by drugs that target cellular transcription. The viral polymerase is also responsible for polyadenylating the 3′ end of viral transcripts, following which they are exported to the cytoplasm for viral protein expression. Replication of the influenza virus genome occurs through the synthesis of full-length complementary copies of the vRNA, the complementary RNA (cRNA). cRNAs are also encapsidated into cRNPs, which in turn act as the template for the polymerase-directed synthesis of progeny vRNPs. Since genome replication is an unprimed reaction and occurs de novo, influenza virus vRNAs and cRNAs possess a 5′ppp.

Evasion of PRR recognition by influenza viruses

If naked cRNAs and vRNAs were generated during the replication of the influenza virus genome, cRNA:vRNA hybridisation would lead to the formation of RIG-I and MDA-5 ligands, activation of the IFN response and restriction of virus replication. To avoid this, influenza virus employs strategies to evade detection by RLRs, thus allowing the virus to replicate efficiently without inducing IFN. Firstly, unlike other RNA viruses that replicate exclusively in the cytoplasm, influenza virus transcription and replication is nuclear. Since RIG-I and MDA-5 are confined to the cytoplasm, nuclear genome replication means that cRNA and progeny vRNAs are generated at a site that is inaccessible to these PRRs. Secondly, the synthesis of full-length cRNA from vRNA and vice versa is very closely coupled to encapsidation; the interaction between the first nucleoprotein monomer and polymerase at 5′ end of the RNA is thought to nucleate the sequence-independent encapsidation of the nascent RNA. Consequently, NP is required for full-length genome amplification. This process also appears to involve cellular factors, since UAP56 and Tat-SF1 interact with NP to promote viral RNA encapsidation. Thus, nascent full-length cRNA and vRNA molecules do not exist as ‘free’ RNA and the formation of cRNA:vRNA hybrids is prevented. Consistent with this, long dsRNAs are undetectable during influenza virus infections and the knockdown of UAP56 leads to an accumulation of dsRNA in infected cells. Thirdly, influenza virus encodes antagonists of the IFN system (reviewed in ). The principal of these is the NS1 protein, which targets multiple components of the IFN induction cascade to limit IFN expression (reviewed in, ). NS1 sequesters dsRNA to limit activation of RLRs, targets TRIM25 to inhibit RIG-I activation and in some influenza virus strains, limits IFN expression post-transcriptionally by interfering with the processing and nuclear export of cellular mRNAs. Other viral proteins have also been described as having IFN-antagonistic properties, including PB1-F2 and the viral polymerase. Nuclear replication, efficient encapsidation of cRNA and vRNA, and IFN antagonism by viral proteins are very effective at preventing activation of the IFN system during infection: studies examining IFN induction in individual cells infected with a range of strains of influenza A virus found that the IFN-β promoter had only been activated in a small proportion of infected cells, both in vitro and in vivo (Fig. 1). Furthermore, activation of the IFN response could not be detected within some developing influenza virus plaques in lung epithelial cells. This may also be the case for influenza viruses that do not express a functional NS1 protein and therefore lack the principal viral IFN antagonist. Such viruses are known to be better inducers of IFN than wild-type viruses, yet demonstrated IFN-β promoter activation in only a fraction of infected cells within the lung epithelia of IFN-β reporter mice infected with a virus lacking the NS1 gene. Thus, the elevated IFN expression induced by this and other NS1-defective viruses relative to wild-type virus is likely to be due to a subset of infected cells (as has been observed for cells infected with a paramyxovirus lacking an IFN antagonist, ), and this is sufficient for the establishment of an antiviral state that impairs the replication of these viruses in IFN-competent systems. The reasons for this cell-to-cell variation in IFN-β promoter activation by influenza are not yet fully resolved, but may be dictated by differences in the nature of the infecting virus particles (i.e. the presence of defective interfering [DI] viruses, which will be discussed later in this review,,,, ), the host cell, or indeed a combination of both, depending on the cell system and the virus used.

In vitro RIG-I ligands

Several different types of RNA have been identified as ligands for RIG-I in the literature (reviewed in ). The presence of a triphosphate at the 5′ end of RNA is now generally accepted as a particularly important characteristic in a RIG-I ligand, although it has been demonstrated recently that RIG-I can additionally trigger IFN induction in response to RNA bearing 5′-diphosphates. Other features such as double-strandedness, length and A/U composition can also define the ability of RNA to induce IFN through RIG-I, irrespective of 5′ phosphates. Although early studies suggested that in vitro transcribed 5′ppp single-stranded RNA (ssRNA) could induce IFN through RIG-I, these results are now thought to be due to the generation of unexpected basepaired RNA products in in vitro transcription reactions, in addition to the expected ssRNA transcript. More recent studies showed that there is a requirement for a region of blunt dsRNA directly adjacent to the 5′ppp; these have since been backed up by structural studies. The minimum length of the double-stranded region required to give 5′ppp-dependent IFN induction has been shown to range from 10 basepairs (bp) to at least 19 bp. Within this short dsRNA stretch, there has been shown to be some tolerance of wobble base-pairs, bulges and mismatches, as found in the ‘panhandle’ genome structures of single-stranded negative-sense RNA viruses. It is noteworthy that there are a number of RNA structures, including 5′OH dsRNAs and 5′ppp dsRNAs with overhanging nucleotides, that can bind to RIG-I yet do not stimulate IFN induction. Indeed, dsRNA with a single overhanging 5′ppp nucleotide, such as those found in some arenavirus genomes, can potently inhibit IFN-β induction by a blunt-ended 5′ppp dsRNA, presumably by competing with blunt-ended 5′ppp dsRNA for RIG-I binding.

The influenza virus ‘panhandle’ as a RIG-I inducer

The 5′ and 3′ termini of the influenza virus genome segments contain sequences of 13 and 12 nucleotides (nt) respectively that are highly conserved across segments and virus subtypes (with the exception of a U4C variation in the 3′ terminus of some genome segments). These sequences possess a partial inverted complementarity, and the influenza virus vRNA segments consequently have the potential to form a ‘panhandle’ structure (Fig. 2A) that is believed to act as the vRNA promoter. NMR, FRET and enzymatic studies of short naked RNAs corresponding to the 3′ and 5′ termini have demonstrated the formation of a stable partial duplex of approximately 15 bp in length between the conserved termini and two to three additional segment-specific bases, through Watson–Crick and non-Watson–Crick basepairing (Fig. 2A). Thus, the influenza virus panhandle has been suggested to be able to act as a potent RIG-I ligand by virtue of the 5′ppp being directly adjacent to a small stretch of partially double-stranded RNA. Although neither the formation of a panhandle structure within a full-length genome segment nor the contribution of terminal base-pairing to IFN induction by influenza virus have yet been directly demonstrated, in vitro transcription products corresponding to influenza virus segments are able to induce IFN when transfected into cells suggesting that the influenza virus vRNAs possess an inherent ability to induce IFN. The observations that RNA extracted from influenza virus-infected cells, from purified influenza virions or from RNP reconstitutions activate the IFN response when transfected into cells in a RIG-I-dependent manner have also been used as evidence for IFN induction by the influenza panhandle. IFN induction by RNA extracted from infected cells is unaffected by RNase III treatment, which digests long dsRNAs into short fragments of 12–15 bp. This may be considered further support for IFN induction by the panhandle, since the base-paired stem would presumably be too short in length to be targeted by this enzyme.

While short free RNAs with the conserved 3′ and 5′ terminal sequences of vRNA forms a panhandle structure, evidence suggests that encapsidated polymerase-bound vRNA does not. Polymerase binding to the vRNA termini causes the formation of a secondary structure, the ‘corkscrew’ conformation, which has been shown by several studies to be critical for viral polymerase activity. In this structure, the very ends of the 5′ and 3′ termini do not associate but instead form intra-termini hairpin loops (Fig. 2B). A highly sensitive single-molecule FRET assay was recently used to examine changes in the structure of short RNAs corresponding to the 5′ and 3′ termini of the genome segments. These RNAs form a partial dsRNA structure in the absence of viral polymerase but undergo a polymerase-dependent conformational change that is consistent with the formation of the corkscrew. The termini of free vRNA therefore form a dsRNA panhandle that is recognised and bound with high affinity by the viral polymerase, causing the vRNA to adopt the corkscrew conformation. Although the corkscrew permits some inter-strand basepairing, this structure would be unlikely to activate RIG-I since the terminal nucleotides do not bind each other to form dsRNA. Furthermore, recent structural determination of an influenza A virus polymerase in complex with the vRNA promoter appears to be incompatible with RIG-I binding of polymerase-associated RNA, since the 5′ppp end of the vRNA is buried within the polymerase in a pocket formed by PA and PB1. In order for an influenza virus genome segment to activate RIG-I therefore, it is likely to exist in the panhandle conformation, which is suggestive of a free, unencapsidated RNA.

The number of vRNA molecules within an infected cell vastly outnumbers cRNA, with the proportion of vRNAs to cRNAs estimated at between 10:1 and 40:1, depending on the segment. For this reason, much of the work on influenza virus RNA and IFN induction has focused on the vRNA. Given that the cRNA is an exact complement of the vRNA, the cRNA termini are also partially complementary and would thus be expected to form panhandle and corkscrew structures. Indeed, cRNPs form closed helical loop structures similar to vRNPs and the formation of a corkscrew structure by the cRNA termini has been demonstrated (Fig. 2C). It is possible that structural differences exist between the vRNA and cRNA promoter structures however, since the wobble basepairs at positions 3 and 5 in the vRNA promoter become mismatched in the cRNA promoter; indeed, the structure of the cRNA promoter has been suggested to be more unstable than that of the vRNA so cRNA and vRNA may differ in the efficiency with which they activate RIG-I.

Identification of RIG-I ligands from infected cells

Naked viral RNAs generated by in vitro transcription reactions or by RNA extractions from infected cells have been shown to induce IFN, yet such free RNAs would not be expected to be generated during virus infections due to vRNA and cRNA encapsidation. Two studies therefore addressed the nature of the ‘genuine’ viral PAMPs responsible for activating RIG-I during influenza virus infections. immunoprecipitated RIG-I from cells infected with an NS1-deficient virus, extracted RIG-I-associated RNA and performed deep sequencing analyses to identify RIG-I ligands. Although sequences mapping to all genome segments could be detected in RIG-I immunoprecipitates, there was particular enrichment for reads mapping to the smallest viral segments M and NS. Furthermore, reads mapping to the PA and PB1 polymerase segments were particularly over-represented in the 5′ and 3′ regions, which is highly suggestive of RNAs derived from genome segments containing large internal deletions. This analysis did not determine whether the RIG-I associated RNAs were vRNA, cRNA or mRNA in nature, since the amplification method used did not permit the retention of strand orientation information.

used a different approach to address the same question. The authors demonstrated the formation of a trimolecular complex of RIG-I, an in vitro RNA transcript and NS1, and by purifying this complex, RNA with IFN-inducing activity could be isolated. A similar complex was postulated to form with the bona fide RIG-I agonist during influenza virus infection, permitting genuine PAMPs from infected cells to be co-precipitated with the NS1 protein. Consistent with this, RNA purified from NS1-immunoprecipitates induced expression from an IFN-β reporter gene in a RIG-I- and 5′ppp-dependent manner, and NS1-associated RNA was enriched for full-length vRNA from all eight segments (in addition to cRNA and mRNA from some segments). Furthermore, RIG-I immunoprecipitates also contained full-length vRNA and cRNA, supporting the authors’ conclusions that full-length genomes constitute the major PAMP in infected cells.

The identification of influenza virus RNA, and in particular vRNA, as ligands of RIG-I in these studies is not surprising, given that the vRNA panhandle possesses the characteristics required for RIG-I activation. What remains to be determined however is how the vRNA panhandle structure is able to form in infected cells, since replication of the virus genome is so closely coupled to encapsidation of the nascent RNA. Two scenarios can be envisaged regarding RIG-I activation during influenza virus infections. The first is that free vRNA, forming a panhandle, is generated erroneously at some point in a virus infection; if this is the case, when and how is this free RNA species generated? The second is that RIG-I can somehow recognise vRNA within the context of a vRNP. Since the polymerase obscures the genome termini, the latter of these scenarios would presumably require displacement of the polymerase from the vRNA promoter for RIG-I recognition. Interestingly, the individual polymerase subunits have been found to associate with RIG-I in an RNA-independent manner; although these associations were not found to have clear implications for activation of the IFN response, it is possible that RIG-I recruitment to the vRNP through polymerase interactions could induce a conformational change in the vRNP structure that leads to formation and exposure of the panhandle.

The requirements for transcription and replication

Since influenza viruses replicate in the nucleus and RIG-I resides in the cytoplasm, incoming and progeny genomes traversing the cytoplasm are the most obvious candidates for triggering IFN induction, and there is some debate about the contribution of each of these to RIG-I activation by influenza viruses. Full-length genome replication requires ongoing viral protein synthesis due to the requirement for concurrent encapsidation by NP and newly synthesised polymerase; the translation inhibitor cycloheximide therefore prevents cRNP and progeny vRNP accumulation (and subsequently secondary viral transcription) in infected cells. reported that no RNA capable of stimulating the IFN-β promoter could be extracted from infected cells in the presence of cycloheximide. Furthermore, they used an RNP reconstitution method to demonstrate IFN induction by reconstitutions with a transcription-defective but not a replication-defective viral polymerase and thus concluded that viral genome replication was required to stimulate IFN expression. However, recent studies have demonstrated IRF3 activation and transcription of both IFN-β and ISG56 genes in conditions where progeny vRNA synthesis is inhibited, either by cycloheximide treatment or using siRNA to NP (Fig. 3).

Incoming viral nucleocapsids have been implicated in RIG-I activation by members of the Bunyaviridae, which also possess segmented negative-sense RNA genomes with a 5′ppp panhandle structure; activation of the IFN induction cascade in the presence of cycloheximide would be consistent with this also being the case for influenza virus infections. Indeed, a recent study has reported the association of vRNPs with RIG-I and MAVS at the mitochondrion at 3 h post-infection. However, several studies have indicated that incoming influenza A vRNPs are not sufficient to induce IFN during infection of epithelial cells and monocyte-derived DCs (moDCs), and that viral RNA synthesis is required. Efficient inhibition of IRF3 and NF-kB activation by the cellular transcription inhibitors actinomycin D and alpha-amanitin in influenza-infected cells strongly suggests that incoming genomes do not function as a major PAMP in lung epithelial cells (Fig. 3). These drugs do not affect the transport of incoming vRNPs to the nucleus, but potently inhibit viral transcription (because of the requirement for cellular transcripts for priming viral mRNA synthesis) and cRNP and vRNP generation (due to inhibition of de novo NP and polymerase synthesis). Virus-mediated IRF3 activation is also inhibited by 5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole (DRB) treatment, which permits viral transcription but impedes the export of viral transcripts from the nucleus. The effects of these drugs on IRF3 activation were specific to influenza viruses, since they have no effect on activation of the IFN induction cascade by the dsRNA analogue poly(I:C) or by paramyxoviruses (Fig. 3) which replicate in the cytoplasm and do not rely on cellular transcription. Moreover, expression of type I and type III IFNs following influenza A virus infection correlates with the accumulation of viral RNAs and can be completely abrogated following inactivation of the virus by heat or UV treatment. The above studies have been limited to a relatively small number of influenza A virus strains, so it is conceivable that different influenza A virus strains may vary in their capacity to be recognised by RIG-I during vRNP entry. Interestingly, influenza B viruses elicit a much more rapid activation of IRF3 than influenza A virus and this activation is insensitive to UV treatment indicating that the incoming genomes of these different virus genera may differ in their ability to be recognised by PRRs.

Taken together, these observations strongly suggest that the generation of the major influenza A virus PAMPs requires the synthesis and nuclear export of an RNA product or products from incoming genomes, and that these RNAs can be generated even in conditions where cRNP and vRNP accumulation is impaired. Nevertheless, it is likely that distinct PAMPs are generated at different stages of the virus life cycle; thus, a minority of incoming influenza A virus genomes may contribute to IFN induction at very early points post-infection, with viral polymerase products (including, but not limited to, progeny genomes) functioning as a more significant PAMP population later in infection. The nature of the PAMPs that are generated in the presence of cycloheximide but not in the presence of cellular transcription inhibitors has not yet been elucidated, and although the sensitivity of IRF3 activation to viral transcription inhibitors may superficially suggest that viral mRNAs can function as IFN inducers, the fact that influenza virus mRNAs are 5′ capped and polyadenylated like host mRNAs makes this unlikely. Moreover, viral mRNAs cannot be detected in RIG-I immunoprecipitations from infected cells, the immunostimulatory activity of RIG-I associated RNA is sensitive to calf intestinal phosphatase treatment (which removes 5′ phosphates), and RNA capable of inducing IFN is still generated in RNP reconstitutions containing a transcription-defective viral polymerase. It is of note that actinomycin D and alpha-amanitin can also affect the nucleocytoplasmic export of viral mRNAs so may also affect export of other viral RNA species; in actinomycin D and alpha-amanitin treatment conditions therefore, viral PAMPs may be retained in the nucleus and thus hidden from RIG-I. It has been suggested that cRNA synthesis from input vRNP templates does not require viral protein synthesis for the initiation of replication per se, but that de novo synthesised polymerase and NP are required to stabilise the cRNA and prevent its degradation by host nucleases. Unencapsidated, unstable cRNAs would therefore be expected to be generated in conditions where polymerase and NP synthesis has been blocked by transcription or translation inhibitors, and these RNAs may be able to activate RIG-I if they were able to reach the cytoplasm.

Defective genomes and IFN induction by influenza virus

The observations that influenza viruses only activate the IFN response in a fraction of infected cells with both wild-type and NS1-defective viruses (Fig. 1) strongly suggest that activation of the IFN induction cascade is not associated with ‘normal’ virus replication, which is perhaps not surprising considering the nuclear localisation of replication and the efficient encapsidation of full-length genomes. The link between the presence of ‘abnormal’ DI genomes and IFN induction by non-segmented negative-strand RNA viruses, including the Paramyxoviridae and Rhabdoviridae, is well known. DI genomes possess deletions that render a DI virus particle unable to complete a full replication cycle due to the absence of the coding region for one or more viral factor that is essential for replication; DI viruses are therefore only able to replicate when a co-infecting non-defective virus is present to supplement the missing viral factor/s. Furthermore, DIs interfere with the multiplication of non-defective virus by competing with non-DI genomes for replication and packaging (reviewed in ). Thus, although DI genomes are considered non-infectious in terms of their inability to generate viral progeny, they can still exert biological effects in host cells. In particular, IFN induction by paramyxoviruses and rhabdoviruses has been associated with ‘copyback’ or ‘snapback’ genome structures that are generated during template-switching of the viral RNA-dependent RNA polymerase between strands of opposite polarity. These structures possess often considerable stretches of dsRNA adjacent to a 5′ppp and are thus very effective RIG-I ligands. Indeed, studies of IFN induction in single cells infected with a paramyxovirus lacking an IFN antagonist have indicated that the IFN-β promoter is not activated by the normal paramyxovirus life cycle, and that only DI-rich virus preparations activated the IFN-β promoter in a majority of cells. It is as yet unclear whether DI genomes themselves are responsible for inducing IFN, since they are encapsidated into stable nucleocapsids and should therefore be hidden from recognition by RIG-I. DI-rich paramyxovirus preparations are potent activators of IRF3 even when progeny genome synthesis has been inhibited by cycloheximide; however, unlike the situation for influenza viruses, the requirements for RNA synthesis to IFN induction by paramyxovirus DI genomes cannot easily be studied using inhibitors of cellular transcription, so it remains to be determined whether input DI genomes are sufficient for this process.

Influenza virus readily generates DI genomes; DI influenza viruses were first identified in the 1950s as ‘incomplete’ non-infectious viruses that were selected for upon serial passage of the virus in embryonated chicken eggs at high multiplicity and they have been described in many studies since (reviewed in, ). In contrast to non-segmented negative-strand RNA viruses, copyback structures are not thought to be generated during influenza virus replication. Instead, influenza DI viruses appear to be limited to internal deletion RNAs that retain the 5′ and 3′ termini of genome segment from which they are derived. Influenza virus DIs can arise from all genome segments, but appear to be more readily detectable from PB2, PB1 and PA segments. The generation of DIs has long been thought of as an artificial laboratory/tissue-culture artefact in laboratory-prepared and egg-derived virus stocks, and their relevance to genuine virus infections in vivo has been questioned. However, several recent studies have suggested an important role for DIs in natural influenza virus infections and in disease outcome. Internal deletion DI viruses similar to those identified in vitro have been detected in samples from infected mice, poultry and humans. Furthermore, DIs are generated de novo during in vivo infections and the transmission of DI viruses between human patients has been described. Evidence is accumulating for an important role of influenza virus DIs in IFN induction. Following a quantitative analysis of different subpopulations of an influenza virus, concluded that IFN-inducing particles are not productively infectious. DI RNA was directly implicated in IFN induction by a study that identified subgenomic RNAs derived from PA and PB1 segments in RIG-I immunoprecipitates from influenza virus-infected cells. Subsequently, studies have correlated the IFN-inducing phenotype of influenza viruses with a propensity to generate or accumulate high numbers of DI genomes in tissue culture. Perez-Cidoncha and colleagues passaged influenza virus through IFN-resistant cells in order to select for mutants that were impaired in their ability to prevent IFN induction or signalling. By this method, a number of mutant viruses were obtained that were stronger IFN inducers than wild-type virus and several of these IFN-inducing mutants were found to accumulate large numbers of DI genomes in infected cells. We have studied the link between influenza virus DIs and IFN induction in tissue culture and found that a preparation of PR8 virus that has been passaged so as to enrich for DI content is a much more efficient activator of the IFN response than our starting virus stock, when cells are infected with either an equivalent amount of total virus particles or plaque-forming virus particles (Fig. 4). Recent in vivo comparisons of the effects of DI-poor or DI-rich influenza virus preparations have shown that the presence of high numbers of DIs is associated with enhanced IFN-β expression in the lungs of infected mice and a reduction in animal morbidity. Moreover, a preparation of influenza virus composed of a single DI species generated by reverse genetics (a internal deletion DI derived from segment 1, ) protects mice against infections by heterologous influenza B virus and paramyxovirus infections. This protection was impaired in mice lacking a functional type I IFN receptor, indicating that this protective effect is mediated at least in part by activation of the IFN response. What remains unclear is why influenza virus DI RNAs should be more effective at inducing IFN than non-defective, full-length genome segments. Due to the requirements for certain sequences at each end of the genome segment for packaging into virions, internal deletion RNAs possess identical 5′ and 3′ termini to non-defective, full-length genomic RNAs and would not therefore be expected to differ in their inherent ability to bind RIG-I. The ability of DI viruses to induce IFN may simply be due to a faster replication rate of DI RNAs than full-length genomes because of their smaller size. Alternatively, DI-mediated interference with viral polymerase and NP expression may lead to a reduction in polymerase-imposed shut-off of cellular gene expression or affect the efficiency of cRNA and vRNA encapsidation. Furthermore, DI-mediated interference may reduce NS1 expression, thereby contributing to IFN induction by limiting IFN antagonism by the virus. This occurs in DI-rich preparations of the paramyxovirus parainfluenza virus 5, where DIs simultaneously stimulate the IFN response and interfere with the expression of the V protein (the viral IFN antagonist) from co-infecting non-defective virus; as a result, the V protein only accumulates in infected cells after the IFN induction cascade has already been activated. Perhaps smaller segments of genomic RNA, such as the internal deletion RNAs and NS and M segment RNAs identified in RIG-I immunoprecipitates, form a panhandle more readily than full-length RNA when they are unencapsidated, or DI RNPs may be less stable than full-length RNPs and thus more prone to releasing free RNA. It is interesting to note that very small flu genome templates can be replicated in the absence of NP; thus, it is a possibility that small DI RNAs could be replicated without being concurrently encapsidated and that these unencapsidated replication products could activate RIG-I.

Concluding remarks

Innate immune responses, including the IFNs, play a critical role in determining the pathogenicity and outcome of an influenza virus infection: efficient activation of the IFN system early in infection effectively restricts viral replication and eliminates the virus, while excessive activation of innate immune responses actually increases tissue damage in the host. Here, we have outlined recent advances in the study of the IFN induction by influenza viruses and the identity of the PAMPs produced during influenza virus infection; however, several unanswered questions remain. Assuming the influenza virus panhandle is recognised by RIG-I during infection, it is unclear how this RNA structure is able to form in infected cells: if the panhandle is formed by free unencapsidated RNA, how and when in the virus life cycle is this RNA generated? Conversely, if the panhandle structure can be formed by RNA encapsidated into RNPs, how are the polymerase and/or NP displaced in order to expose the genome termini? What are the viral PAMPs that are generated in conditions when progeny genome synthesis has been blocked? What are the reasons for the cell-to-cell differences in activation of the IFN promoter during influenza virus infections in vitro and in vivo? Lastly, why are influenza DIs better able to induce IFN than non-defective virus? Multiple factors are likely to influence IFN induction by influenza virus during an infection, including the rate of virus replication, its ability to actively antagonise IFN induction, the rate of DI generation by the viral polymerase and also factors conferred by the host; by gaining a broader comprehension of all of these contributing elements, we can more fully understand the interactions between influenza virus and the IFN system and apply this understanding to the development of novel anti-influenza therapies.

References 184

  1. 1.

    Amorim M.J., Read E.K., Dalton R.M., Medcalf L., Digard P. Nuclear export of influenza A virus mRNAs requires ongoing RNA polymerase II activity. Traffic. 2007;8(1):1-11.

    Not in our library10.1111/j.1600-0854.2006.00507.x

  2. 2.

    Azzeh M., Flick R., Hobom G. Functional analysis of the influenza A virus cRNA promoter and construction of an ambisense transcription system. Virology. 2001;289(2):400-410.

    Not in our library10.1006/viro.2001.1107

  3. 3.

    Bae S.H., Cheong H.K., Lee J.H., Cheong C., Kainosho M., Choi B.S. Structural features of an influenza virus promoter and their implications for viral RNA synthesis. Proc. Natl. Acad. Sci. U. S. A. 2001;98(19):10602-10607.

    Not in our library10.1073/pnas.191268798

  4. 4.

    Barrett T., Wolstenholme A.J., Mahy B.W. Transcription and replication of influenza virus RNA. Virology. 1979;98(1):211-225.

    Not in our library10.1016/0042-6822(79)90539-7

  5. 5.

    Baskin C.R., Bielefeldt-Ohmann H., Tumpey T.M., Sabourin P.J., Long J.P., Garcia-Sastre A., Tolnay A.E., Albrecht R., Pyles J.A., Olson P.H., Aicher L.D., Rosenzweig E.R., Murali-Krishna K., Clark E.A., Kotur M.S., Fornek J.L., Proll S., Palermo R.E., Sabourin C.L., Katze M.G. Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proc. Natl. Acad. Sci. U. S. A. 2009;106(9):3455-3460.

    Not in our library10.1073/pnas.0813234106

  6. 6.

    Baudin F., Bach C., Cusack S., Ruigrok R.W. Structure of influenza virus RNP. I. Influenza virus nucleoprotein melts secondary structure in panhandle RNA and exposes the bases to the solvent. EMBO J. 1994;13(13):3158-3165.

    Not in our library10.1002/j.1460-2075.1994.tb06614.x

  7. 7.

    Baum A., Sachidanandam R., Garcia-Sastre A. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc. Natl. Acad. Sci. U. S. A. 2010;107(37):16303-16308.

    Not in our library10.1073/pnas.1005077107

  8. 8.

    Binder M., Eberle F., Seitz S., Mucke N., Huber C.M., Kiani N., Kaderali L., Lohmann V., Dalpke A., Bartenschlager R. Molecular mechanism of signal perception and integration by the innate immune sensor retinoic acid-inducible gene-I (RIG-I). J. Biol. Chem. 2011;286(31):27278-27287.

    Not in our library10.1074/jbc.m111.256974

  9. 9.

    Bonin M., Oberstrass J., Lukacs N., Ewert K., Oesterschulze E., Kassing R., Nellen W. Determination of preferential binding sites for anti-dsRNA antibodies on double-stranded RNA by scanning force microscopy. RNA. 2000;6(4):563-570.

    Not in our library10.1017/s1355838200992318

  10. 10.

    Brass A.L., Huang I.C., Benita Y., John S.P., Krishnan M.N., Feeley E.M., Ryan B.J., Weyer J.L., van der Weyden L., Fikrig E., Adams D.J., Xavier R.J., Farzan M., Elledge S.J. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell. 2009;139(7):1243-1254.

    Not in our library10.1016/j.cell.2009.12.017

  11. 11.

    Brownlee G.G., Sharps J.L. The RNA polymerase of influenza a virus is stabilized by interaction with its viral RNA promoter. J. Virol. 2002;76(14):7103-7113.

    Not in our library10.1128/jvi.76.14.7103-7113.2002

  12. 12.

    Cazenave C., Uhlenbeck O.C. RNA template-directed RNA synthesis by T7 RNA polymerase. Proc. Natl. Acad. Sci. U. S. A. 1994;91(15):6972-6976.

    Not in our library10.1073/pnas.91.15.6972

  13. 13.

    Chan A.Y., Vreede F.T., Smith M., Engelhardt O.G., Fodor E. Influenza virus inhibits RNA polymerase II elongation. Virology. 2006;351(1):210-217.

    Not in our library10.1016/j.virol.2006.03.005

  14. 14.

    Chen S., Short J.A., Young D.F., Killip M.J., Schneider M., Goodbourn S., Randall R.E. Heterocellular induction of interferon by negative-sense RNA viruses. Virology. 2010;407(2):247-255.

    Not in our library10.1016/j.virol.2010.08.008

  15. 15.

    Cheong H.K., Cheong C., Choi B.S. Secondary structure of the panhandle RNA of influenza virus A studied by NMR spectroscopy. Nucleic Acids Res. 1996;24(21):4197-4201.

    Not in our library10.1093/nar/24.21.4197

  16. 16.

    Cheong H.K., Cheong C., Lee Y.S., Seong B.L., Choi B.S. Structure of influenza virus panhandle RNA studied by NMR spectroscopy and molecular modeling. Nucleic Acids Res. 1999;27(5):1392-1397.

    Not in our library10.1093/nar/27.5.1392

  17. 17.

    Cheung C.Y., Poon L.L., Lau A.S., Luk W., Lau Y.L., Shortridge K.F., Gordon S., Guan Y., Peiris J.S. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease. Lancet. 2002;360(9348):1831-1837.

    Not in our library10.1016/s0140-6736(02)11772-7

  18. 18.

    Childs K., Randall R., Goodbourn S. Paramyxovirus V proteins interact with the RNA Helicase LGP2 to inhibit RIG-I-dependent interferon induction. J. Virol. 2012;86(7):3411-3421.

    Not in our library10.1128/jvi.06405-11

  19. 19.

    Childs K.S., Randall R.E., Goodbourn S. LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA. PLoS ONE. 2013;8(5):e64202.

    Not in our library10.1371/journal.pone.0064202

  20. 20.
    Type I and Type III Interferons Drive Redundant Amplification Loops to Induce a Transcriptional Signature in Influenza-Infected Airway Epithelia · 2013
    No notice
  21. 21.

    Crow M., Deng T., Addley M., Brownlee G.G. Mutational analysis of the influenza virus cRNA promoter and identification of nucleotides critical for replication. J. Virol. 2004;78(12):6263-6270.

    Not in our library10.1128/jvi.78.12.6263-6270.2004

  22. 22.

    Davis W.G., Bowzard J.B., Sharma S.D., Wiens M.E., Ranjan P., Gangappa S., Stuchlik O., Pohl J., Donis R.O., Katz J.M., Cameron C.E., Fujita T., Sambhara S. The 3′ untranslated regions of influenza genomic sequences are 5′PPP-independent ligands for RIG-I. PLoS ONE. 2012;7(3):e32661.

    Not in our library10.1371/journal.pone.0032661

  23. 23.
    IFITM3 Restricts Influenza A Virus Entry by Blocking the Formation of Fusion Pores following Virus-Endosome Hemifusion · 2014
    No notice
  24. 24.

    Desselberger U., Racaniello V.R., Zazra J.J., Palese P. The 3′ and 5′-terminal sequences of influenza A, B and C virus RNA segments are highly conserved and show partial inverted complementarity. Gene. 1980;8(3):315-328.

    Not in our library10.1016/0378-1119(80)90007-4

  25. 25.

    Diebold S.S., Kaisho T., Hemmi H., Akira S., Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303(5663):1529-1531.

    Not in our library10.1126/science.1093616

  26. 26.

    Dimmock N.J., Easton A.J. Defective interfering influenza virus RNAs: time to reevaluate their clinical potential as broad-spectrum antivirals? J. Virol. 2014;88(10):5217-5227.

    Not in our library10.1128/jvi.03193-13

  27. 27.

    Dimmock N.J., Rainsford E.W., Scott P.D., Marriott A.C. Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral. J. Virol. 2008;82(17):8570-8578.

    Not in our library10.1128/jvi.00743-08

  28. 28.

    Donelan N.R., Basler C.F., Garcia-Sastre A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J. Virol. 2003;77(24):13257-13266.

    Not in our library10.1128/jvi.77.24.13257-13266.2003

  29. 29.

    Dudek S.E., Wixler L., Nordhoff C., Nordmann A., Anhlan D., Wixler V., Ludwig S. The influenza virus PB1-F2 protein has interferon antagonistic activity. Biol. Chem. 2011;392(12):1135-1144.

    Not in our library10.1515/bc.2011.174

  30. 30.

    Easton A.J., Scott P.D., Edworthy N.L., Meng B., Marriott A.C., Dimmock N.J. A novel broad-spectrum treatment for respiratory virus infections: influenza-based defective interfering virus provides protection against pneumovirus infection in vivo. Vaccine. 2011;29(15):2777-2784.

    Not in our library10.1016/j.vaccine.2011.01.102

  31. 31.

    Egorov A., Brandt S., Sereinig S., Romanova J., Ferko B., Katinger D., Grassauer A., Alexandrova G., Katinger H., Muster T. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J. Virol. 1998;72(8):6437-6441.

    Not in our library10.1128/jvi.72.8.6437-6441.1998

  32. 32.

    Engel D.A. The influenza virus NS1 protein as a therapeutic target. Antivir. Res. 2013;99(3):409-416.

    Not in our library10.1016/j.antiviral.2013.06.005

  33. 33.

    Everitt A.R., Clare S., Pertel T., John S.P., Wash R.S., Smith S.E., Chin C.R., Feeley E.M., Sims J.S., Adams D.J., Wise H.M., Kane L., Goulding D., Digard P., Anttila V., Baillie J.K., Walsh T.S., Hume D.A., Palotie A., Xue Y., Colonna V., Tyler-Smith C., Dunning J., Gordon S.B., Smyth R.L., Openshaw P.J., Dougan G., Brass A.L., Kellam P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012;484(7395):519-523.

    Not in our library10.1038/nature10921

  34. 34.
    IFITM3 Inhibits Influenza A Virus Infection by Preventing Cytosolic Entry · 2011
    No notice
  35. 35.

    Flick R., Hobom G. Interaction of influenza virus polymerase with viral RNA in the ‘corkscrew’ conformation. J. Gen. Virol. 1999;80(Pt. 10):2565-2572.

    Not in our library10.1099/0022-1317-80-10-2565

  36. 36.

    Flick R., Neumann G., Hoffmann E., Neumeier E., Hobom G. Promoter elements in the influenza vRNA terminal structure. RNA. 1996;2(10):1046-1057.

    Not in our library

  37. 37.

    Fodor E. The RNA polymerase of influenza a virus: mechanisms of viral transcription and replication. Acta Virol. 2013;57(2):113-122.

    Not in our library10.4149/av_2013_02_113

  38. 38.

    Fodor E., Pritlove D.C., Brownlee G.G. The influenza virus panhandle is involved in the initiation of transcription. J. Virol. 1994;68(6):4092-4096.

    Not in our library10.1128/jvi.68.6.4092-4096.1994

  39. 39.

    Fodor E., Pritlove D.C., Brownlee G.G. Characterization of the RNA-fork model of virion RNA in the initiation of transcription in influenza A virus. J. Virol. 1995;69(7):4012-4019.

    Not in our library10.1128/jvi.69.7.4012-4019.1995

  40. 40.

    Fortes P., Beloso A., Ortin J. Influenza virus NS1 protein inhibits pre-mRNA splicing and blocks mRNA nucleocytoplasmic transport. EMBO J. 1994;13(3):704-712.

    Not in our library10.1002/j.1460-2075.1994.tb06310.x

  41. 41.

    Frensing T., Pflugmacher A., Bachmann M., Peschel B., Reichl U. Impact of defective interfering particles on virus replication and antiviral host response in cell culture-based influenza vaccine production. Appl. Microbiol. Biotechnol. 2014;98(21):8999-9008.

    Not in our library10.1007/s00253-014-5933-y

  42. 42.

    Gack M.U. Mechanisms of RIG-I-like receptor activation and manipulation by viral pathogens. J. Virol. 2014;88(10):5213-5216.

    Not in our library10.1128/jvi.03370-13

  43. 43.

    Gack M.U., Albrecht R.A., Urano T., Inn K.S., Huang I.C., Carnero E., Farzan M., Inoue S., Jung J.U., Garcia-Sastre A. Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe. 2009;5(5):439-449.

    Not in our library10.1016/j.chom.2009.04.006

  44. 44.

    Gack M.U., Shin Y.C., Joo C.H., Urano T., Liang C., Sun L., Takeuchi O., Akira S., Chen Z., Inoue S., Jung J.U. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 2007;446(7138):916-920.

    Not in our library10.1038/nature05732

  45. 45.

    Gao S., von der Malsburg A., Dick A., Faelber K., Schroder G.F., Haller O., Kochs G., Daumke O. Structure of myxovirus resistance protein a reveals intra- and intermolecular domain interactions required for the antiviral function. Immunity. 2011;35(4):514-525.

    Not in our library10.1016/j.immuni.2011.07.012

  46. 46.

    Garcia-Sastre A. Induction and evasion of type I interferon responses by influenza viruses. Virus Res. 2011;162(1–2):12-18.

    Not in our library10.1016/j.virusres.2011.10.017

  47. 47.

    Garcia-Sastre A., Egorov A., Matassov D., Brandt S., Levy D.E., Durbin J.E., Palese P., Muster T. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology. 1998;252(2):324-330.

    Not in our library10.1006/viro.1998.9508

  48. 48.

    Gerber M., Isel C., Moules V., Marquet R. Selective packaging of the influenza A genome and consequences for genetic reassortment. Trends Microbiol. 2014;22(8):446-455.

    Not in our library10.1016/j.tim.2014.04.001

  49. 49.

    Goubau D., Schlee M., Deddouche S., Pruijssers A.J., Zillinger T., Goldeck M., Schuberth C., Van der Veen A.G., Fujimura T., Rehwinkel J., Iskarpatyoti J.A., Barchet W., Ludwig J., Dermody T.S., Hartmann G., Reis E.S.C. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates. Nature. 2014;514(7522):372-375.

    Not in our library10.1038/nature13590

  50. 50.

    Graef K.M., Vreede F.T., Lau Y.F., McCall A.W., Carr S.M., Subbarao K., Fodor E. The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon. J. Virol. 2010;84(17):8433-8445.

    Not in our library10.1128/jvi.00879-10

  51. 51.

    Guillot L., Le Goffic R., Bloch S., Escriou N., Akira S., Chignard M., Si-Tahar M. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J. Biol. Chem. 2005;280(7):5571-5580.

    Not in our library10.1074/jbc.m410592200

  52. 52.

    Hale B.G., Randall R.E., Ortin J., Jackson D. The multifunctional NS1 protein of influenza A viruses. J. Gen. Virol. 2008;89(Pt 10):2359-2376.

    Not in our library10.1099/vir.0.2008/004606-0

  53. 53.

    Haller O., Arnheiter H., Lindenmann J., Gresser I. Host gene influences sensitivity to interferon action selectively for influenza virus. Nature. 1980;283(5748):660-662.

    Not in our library10.1038/283660a0

  54. 54.

    Hatada E., Hasegawa M., Mukaigawa J., Shimizu K., Fukuda R. Control of influenza virus gene expression: quantitative analysis of each viral RNA species in infected cells. J. Biochem. 1989;105(4):537-546.

    Not in our library10.1093/oxfordjournals.jbchem.a122702

  55. 55.

    Hausmann S., Marq J.B., Tapparel C., Kolakofsky D., Garcin D. RIG-I and dsRNA-induced IFNbeta activation. PLoS ONE. 2008;3(12):e3965.

    Not in our library10.1371/journal.pone.0003965

  56. 56.

    Hay A.J., Lomniczi B., Bellamy A.R., Skehel J.J. Transcription of the influenza virus genome. Virology. 1977;83(2):337-355.

    Not in our library10.1016/0042-6822(77)90179-9

  57. 57.

    Hayman A., Comely S., Lackenby A., Murphy S., McCauley J., Goodbourn S., Barclay W. Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway. Virology. 2006;347(1):52-64.

    Not in our library10.1016/j.virol.2005.11.024

  58. 58.
    Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia · 2013
    Corrected
  59. 59.

    Honda A., Ueda K., Nagata K., Ishihama A. RNA polymerase of influenza virus: role of NP in RNA chain elongation. J. Biochem. 1988;104(6):1021-1026.

    Not in our library10.1093/oxfordjournals.jbchem.a122569

  60. 60.

    Hornung V., Ellegast J., Kim S., Brzozka K., Jung A., Kato H., Poeck H., Akira S., Conzelmann K.K., Schlee M., Endres S., Hartmann G. 5′-Triphosphate RNA is the ligand for RIG-I. Science. 2006;314(5801):994-997.

    Not in our library10.1126/science.1132505

  61. 61.

    Hsu M.T., Parvin J.D., Gupta S., Krystal M., Palese P. Genomic RNAs of influenza viruses are held in a circular conformation in virions and in infected cells by a terminal panhandle. Proc. Natl. Acad. Sci. U. S. A. 1987;84(22):8140-8144.

    Not in our library10.1073/pnas.84.22.8140

  62. 62.

    Husser L., Alves M.P., Ruggli N., Summerfield A. Identification of the role of RIG-I, MDA-5 and TLR3 in sensing RNA viruses in porcine epithelial cells using lentivirus-driven RNA interference. Virus Res. 2011;159(1):9-16.

    Not in our library10.1016/j.virusres.2011.04.005

  63. 63.

    Ioannidis I., Ye F., McNally B., Willette M., Flano E. Toll-like receptor expression and induction of type I and type III interferons in primary airway epithelial cells. J. Virol. 2013;87(6):3261-3270.

    Not in our library10.1128/jvi.01956-12

  64. 64.

    Iwai A., Shiozaki T., Kawai T., Akira S., Kawaoka Y., Takada A., Kida H., Miyazaki T. Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1. J. Biol. Chem. 2010;285(42):32064-32074.

    Not in our library10.1074/jbc.m110.112458

  65. 65.

    Jackson D., Killip M.J., Galloway C.S., Russell R.J., Randall R.E. Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K). Virology. 2010;396(1):94-105.

    Not in our library10.1016/j.virol.2009.10.004

  66. 66.

    Jewell N.A., Cline T., Mertz S.E., Smirnov S.V., Flano E., Schindler C., Grieves J.L., Durbin R.K., Kotenko S.V., Durbin J.E. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J. Virol. 2010;84(21):11515-11522.

    Not in our library10.1128/jvi.01703-09

  67. 67.

    Jewell N.A., Vaghefi N., Mertz S.E., Akter P., Peebles R.S., Bakaletz L.O., Durbin R.K., Flano E., Durbin J.E. Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J. Virol. 2007;81(18):9790-9800.

    Not in our library10.1128/jvi.00530-07

  68. 68.

    Johnston M.D. The characteristics required for a Sendai virus preparation to induce high levels of interferon in human lymphoblastoid cells. J. Gen. Virol. 1981;56(Pt. 1):175-184.

    Not in our library10.1099/0022-1317-56-1-175

  69. 69.

    Jonges M., Welkers M.R., Jeeninga R.E., Meijer A., Schneeberger P., Fouchier R.A., de Jong M.D., Koopmans M. Emergence of the virulence-associated PB2 E627 K substitution in a fatal human case of highly pathogenic avian influenza virus A (H7N7) infection as determined by Illumina ultra-deep sequencing. J. Virol. 2014;88(3):1694-1702.

    Not in our library10.1128/jvi.02044-13

  70. 70.
    Genetic trans-Complementation Establishes a New Model for Influenza Virus RNA Transcription and Replication · 2009
    No notice
  71. 71.

    Kallfass C., Lienenklaus S., Weiss S., Staeheli P. Visualizing the beta interferon response in mice during infection with influenza A viruses expressing or lacking nonstructural protein 1. J. Virol. 2013;87(12):6925-6930.

    Not in our library10.1128/jvi.00283-13

  72. 72.

    Kaminski M.M., Ohnemus A., Cornitescu M., Staeheli P. Plasmacytoid dendritic cells and Toll-like receptor 7-dependent signalling promote efficient protection of mice against highly virulent influenza A virus. J. Gen. Virol. 2012;93(Pt. 3):555-559.

    Not in our library10.1099/vir.0.039065-0

  73. 73.

    Karpala A.J., Stewart C., McKay J., Lowenthal J.W., Bean A.G. Characterization of chicken Mda5 activity: regulation of IFN-beta in the absence of RIG-I functionality. J. Immunol. 2011;186(9):5397-5405.

    Not in our library10.4049/jimmunol.1003712

  74. 74.

    Kash J.C., Tumpey T.M., Proll S.C., Carter V., Perwitasari O., Thomas M.J., Basler C.F., Palese P., Taubenberger J.K., Garcia-Sastre A., Swayne D.E., Katze M.G. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature. 2006;443(7111):578-581.

    Not in our library10.1038/nature05181

  75. 75.

    Kato H., Sato S., Yoneyama M., Yamamoto M., Uematsu S., Matsui K., Tsujimura T., Takeda K., Fujita T., Takeuchi O., Akira S. Cell type-specific involvement of RIG-I in antiviral response. Immunity. 2005;23(1):19-28.

    Not in our library10.1016/j.immuni.2005.04.010

  76. 76.

    Kato H., Takeuchi O., Mikamo-Satoh E., Hirai R., Kawai T., Matsushita K., Hiiragi A., Dermody T.S., Fujita T., Akira S. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 2008;205(7):1601-1610.

    Not in our library10.1084/jem.20080091

  77. 77.

    Kato H., Takeuchi O., Sato S., Yoneyama M., Yamamoto M., Matsui K., Uematsu S., Jung A., Kawai T., Ishii K.J., Yamaguchi O., Otsu K., Tsujimura T., Koh C.S., Reis e Sousa C., Matsuura Y., Fujita T., Akira S. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441(7089):101-105.

    Not in our library10.1038/nature04734

  78. 78.

    Khaitov M.R., Laza-Stanca V., Edwards M.R., Walton R.P., Rohde G., Contoli M., Papi A., Stanciu L.A., Kotenko S.V., Johnston S.L. Respiratory virus induction of alpha-, beta- and lambda-interferons in bronchial epithelial cells and peripheral blood mononuclear cells. Allergy. 2009;64(3):375-386.

    Not in our library10.1111/j.1398-9995.2008.01826.x

  79. 79.

    Killip M.J., Smith M., Jackson D., Randall R.E. Activation of the interferon induction cascade by influenza a viruses requires viral RNA synthesis and nuclear export. J. Virol. 2014;88(8):3942-3952.

    Not in our library10.1128/jvi.03109-13

  80. 80.

    Killip M.J., Young D.F., Gatherer D., Ross C.S., Short J.A., Davison A.J., Goodbourn S., Randall R.E. Deep sequencing analysis of defective genomes of parainfluenza virus 5 and their role in interferon induction. J. Virol. 2013;87(9):4798-4807.

    Not in our library10.1128/jvi.03383-12

  81. 81.

    Killip M.J., Young D.F., Precious B.L., Goodbourn S., Randall R.E. Activation of the beta interferon promoter by paramyxoviruses in the absence of virus protein synthesis. J. Gen. Virol. 2012;93(Pt. 2):299-307.

    Not in our library10.1099/vir.0.037531-0

  82. 82.

    Killip M.J., Young D.F., Ross C.S., Chen S., Goodbourn S., Randall R.E. Failure to activate the IFN-beta promoter by a paramyxovirus lacking an interferon antagonist. Virology. 2011;415(1):39-46.

    Not in our library10.1016/j.virol.2011.03.027

  83. 83.

    Kim D.H., Longo M., Han Y., Lundberg P., Cantin E., Rossi J.J. Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase. Nat. Biotechnol. 2004;22(3):321-325.

    Not in our library10.1038/nbt940

  84. 84.

    Kochs G., Martinez-Sobrido L., Lienenklaus S., Weiss S., Garcia-Sastre A., Staeheli P. Strong interferon-inducing capacity of a highly virulent variant of influenza A virus strain PR8 with deletions in the NS1 gene. J. Gen. Virol. 2009;90(Pt. 12):2990-2994.

    Not in our library10.1099/vir.0.015727-0

  85. 85.

    Kohlway A., Luo D., Rawling D.C., Ding S.C., Pyle A.M. Defining the functional determinants for RNA surveillance by RIG-I. EMBO Rep. 2013;14(9):772-779.

    Not in our library10.1038/embor.2013.108

  86. 86.

    Kolakofsky D., Kowalinski E., Cusack S. A structure-based model of RIG-I activation. RNA. 2012;18(12):2118-2127.

    Not in our library10.1261/rna.035949.112

  87. 87.

    Kowalinski E., Lunardi T., McCarthy A.A., Louber J., Brunel J., Grigorov B., Gerlier D., Cusack S. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell. 2011;147(2):423-435.

    Not in our library10.1016/j.cell.2011.09.039

  88. 88.

    Koyama S., Ishii K.J., Kumar H., Tanimoto T., Coban C., Uematsu S., Kawai T., Akira S. Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J. Immunol. 2007;179(7):4711-4720.

    Not in our library10.4049/jimmunol.179.7.4711

  89. 89.

    Kumar H., Kawai T., Kato H., Sato S., Takahashi K., Coban C., Yamamoto M., Uematsu S., Ishii K.J., Takeuchi O., Akira S. Essential role of IPS-1 in innate immune responses against RNA viruses. J. Exp. Med. 2006;203(7):1795-1803.

    Not in our library10.1084/jem.20060792

  90. 90.

    Kuniyoshi K., Takeuchi O., Pandey S., Satoh T., Iwasaki H., Akira S., Kawai T. Pivotal role of RNA-binding E3 ubiquitin ligase MEX3C in RIG-I-mediated antiviral innate immunity. Proc. Natl. Acad. Sci. U. S. A. 2014;111(15):5646-5651.

    Not in our library10.1073/pnas.1401674111

  91. 91.

    Lamb R.A., Parks G.D., Knipe D.M., Howley P.M. Paramyxoviridae. Fields Virology. 2013;957-995.

    Not in our library

  92. 92.

    Le Goffic R., Pothlichet J., Vitour D., Fujita T., Meurs E., Chignard M., Si-Tahar M. Cutting edge: influenza A virus activates TLR3-dependent inflammatory and RIG-I-dependent antiviral responses in human lung epithelial cells. J. Immunol. 2007;178(6):3368-3372.

    Not in our library10.4049/jimmunol.178.6.3368

  93. 93.

    Leahy M.B., Dobbyn H.C., Brownlee G.G. Hairpin loop structure in the 3′ arm of the influenza A virus virion RNA promoter is required for endonuclease activity. J. Virol. 2001;75(15):7042-7049.

    Not in our library10.1128/jvi.75.15.7042-7049.2001

  94. 94.

    Leahy M.B., Pritlove D.C., Poon L.L., Brownlee G.G. Mutagenic analysis of the 5′ arm of the influenza A virus virion RNA promoter defines the sequence requirements for endonuclease activity. J. Virol. 2001;75(1):134-142.

    Not in our library10.1128/jvi.75.1.134-142.2001

  95. 95.

    Lester S.N., Li K. Toll-like receptors in antiviral innate immunity. J. Mol. Biol. 2014;426(6):1246-1264.

    Not in our library10.1016/j.jmb.2013.11.024

  96. 96.
    IFITM Proteins Restrict Viral Membrane Hemifusion · 2013
    No notice
  97. 97.

    Li W., Chen H., Sutton T., Obadan A., Perez D.R. Interactions between the influenza A virus RNA polymerase components and retinoic acid-inducible gene I. J. Virol. 2014;88(18):10432-10447.

    Not in our library10.1128/jvi.01383-14

  98. 98.

    Liedmann S., Hrincius E.R., Guy C., Anhlan D., Dierkes R., Carter R., Wu G., Staeheli P., Green D.R., Wolff T., McCullers J.A., Ludwig S., Ehrhardt C. Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions. Nat. Commun. 2014;5:5645.

    Not in our library10.1038/ncomms6645

  99. 99.

    Liniger M., Summerfield A., Zimmer G., McCullough K.C., Ruggli N. Chicken cells sense influenza A virus infection through MDA5 and CARDIF signaling involving LGP2. J. Virol. 2012;86(2):705-717.

    Not in our library10.1128/jvi.00742-11

  100. 100.

    Loo Y.M., Fornek J., Crochet N., Bajwa G., Perwitasari O., Martinez-Sobrido L., Akira S., Gill M.A., Garcia-Sastre A., Katze M.G., Gale M. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J. Virol. 2008;82(1):335-345.

    Not in our library10.1128/jvi.01080-07

  101. 101.

    Lu C., Xu H., Ranjith-Kumar C.T., Brooks M.T., Hou T.Y., Hu F., Herr A.B., Strong R.K., Kao C.C., Li P. The structural basis of 5′ triphosphate double-stranded RNA recognition by RIG-I C-terminal domain. Structure. 2010;18(8):1032-1043.

    Not in our library10.1016/j.str.2010.05.007

  102. 102.

    Lund J.M., Alexopoulou L., Sato A., Karow M., Adams N.C., Gale N.W., Iwasaki A., Flavell R.A. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. U. S. A. 2004;101(15):5598-5603.

    Not in our library10.1073/pnas.0400937101

  103. 103.

    Luo D., Ding S.C., Vela A., Kohlway A., Lindenbach B.D., Pyle A.M. Structural insights into RNA recognition by RIG-I. Cell. 2011;147(2):409-422.

    Not in our library10.1016/j.cell.2011.09.023

  104. 104.

    Mahy B.W., Barrett T., Briedis D.J., Brownson J.M., Wolstenholme A.J. Influence of the host cell on influenza virus replication. Philos. Trans. R. Soc. Lond. B: Biol. Sci. 1980;288(1029):349-357.

    Not in our library10.1098/rstb.1980.0011

  105. 105.

    Malathi K., Dong B., Gale M., Silverman R.H. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature. 2007;448(7155):816-819.

    Not in our library10.1038/nature06042

  106. 106.

    Malathi K., Saito T., Crochet N., Barton D.J., Gale M., Silverman R.H. RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP. RNA. 2010;16(11):2108-2119.

    Not in our library10.1261/rna.2244210

  107. 107.

    Marcus P.I., Gaccione C. Interferon induction by viruses. XIX. Vesicular stomatitis virus – New Jersey: high multiplicity passages generate interferon-inducing, defective-interfering particles. Virology. 1989;171(2):630-633.

    Not in our library10.1016/0042-6822(89)90637-5

  108. 108.

    Marcus P.I., Rojek J.M., Sekellick M.J. Interferon induction and/or production and its suppression by influenza A viruses. J. Virol. 2005;79(5):2880-2890.

    Not in our library10.1128/jvi.79.5.2880-2890.2005

  109. 109.

    Mark G.E., Taylor J.M., Broni B., Krug R.M. Nuclear accumulation of influenza viral RNA transcripts and the effects of cycloheximide, actinomycin D, and alpha-amanitin. J. Virol. 1979;29(2):744-752.

    Not in our library10.1128/jvi.29.2.744-752.1979

  110. 110.

    Marq J.B., Hausmann S., Veillard N., Kolakofsky D., Garcin D. Short double-stranded RNAs with an overhanging 5′ ppp-nucleotide, as found in arenavirus genomes, act as RIG-I decoys. J. Biol. Chem. 2011;286(8):6108-6116.

    Not in our library10.1074/jbc.m110.186262

  111. 111.

    Marriott A.C., Dimmock N.J. Defective interfering viruses and their potential as antiviral agents. Rev. Med. Virol. 2010;20(1):51-62.

    Not in our library10.1002/rmv.641

  112. 112.

    Mayer A.K., Muehmer M., Mages J., Gueinzius K., Hess C., Heeg K., Bals R., Lang R., Dalpke A.H. Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells. J. Immunol. 2007;178(5):3134-3142.

    Not in our library10.4049/jimmunol.178.5.3134

  113. 113.

    Mena I., Jambrina E., Albo C., Perales B., Ortin J., Arrese M., Vallejo D., Portela A. Mutational analysis of influenza A virus nucleoprotein: identification of mutations that affect RNA replication. J. Virol. 1999;73(2):1186-1194.

    Not in our library10.1128/jvi.73.2.1186-1194.1999

  114. 114.

    Momose F., Basler C.F., O’Neill R.E., Iwamatsu A., Palese P., Nagata K. Cellular splicing factor RAF-2p48/NPI-5/BAT1/UAP56 interacts with the influenza virus nucleoprotein and enhances viral RNA synthesis. J. Virol. 2001;75(4):1899-1908.

    Not in our library10.1128/jvi.75.4.1899-1908.2001

  115. 115.

    Mordstein M., Neugebauer E., Ditt V., Jessen B., Rieger T., Falcone V., Sorgeloos F., Ehl S., Mayer D., Kochs G., Schwemmle M., Gunther S., Drosten C., Michiels T., Staeheli P. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J. Virol. 2010;84(11):5670-5677.

    Not in our library10.1128/jvi.00272-10

  116. 116.

    Mukaigawa J., Hatada E., Fukuda R., Shimizu K. Involvement of the influenza A virus PB2 protein in the regulation of viral gene expression. J. Gen. Virol. 1991;72(Pt. 11):2661-2670.

    Not in our library10.1099/0022-1317-72-11-2661

  117. 117.

    Naito T., Kiyasu Y., Sugiyama K., Kimura A., Nakano R., Matsukage A., Nagata K. An influenza virus replicon system in yeast identified Tat-SF1 as a stimulatory host factor for viral RNA synthesis. Proc. Natl. Acad. Sci. U. S. A. 2007;104(46):18235-18240.

    Not in our library10.1073/pnas.0705856104

  118. 118.

    Nayak D.P. Defective interfering influenza viruses. Annu. Rev. Microbiol. 1980;34:619-644.

    Not in our library10.1146/annurev.mi.34.100180.003155

  119. 119.

    Nemeroff M.E., Barabino S.M., Li Y., Keller W., Krug R.M. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′ end formation of cellular pre-mRNAs. Mol. Cell. 1998;1(7):991-1000.

    Not in our library10.1016/s1097-2765(00)80099-4

  120. 120.

    Ngunjiri J.M., Buchek G.M., Mohni K.N., Sekellick M.J., Marcus P.I. Influenza virus subpopulations: exchange of lethal H5N1 virus NS for H1N1 virus NS triggers de novo generation of defective-interfering particles and enhances interferon-inducing particle efficiency. J. Interferon Cytokine Res. 2013;33(3):99-107.

    Not in our library10.1089/jir.2012.0070

  121. 121.

    Ngunjiri J.M., Lee C.W., Ali A., Marcus P.I. Influenza virus interferon-inducing particle efficiency is reversed in avian and mammalian cells, and enhanced in cells co-infected with defective-interfering particles. J. Interferon Cytokine Res. 2012;32(6):280-285.

    Not in our library10.1089/jir.2011.0102

  122. 122.

    Noah D.L., Twu K.Y., Krug R.M. Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS. Virology. 2003;307(2):386-395.

    Not in our library10.1016/s0042-6822(02)00127-7

  123. 123.

    Noble E., Mathews D.H., Chen J.L., Turner D.H., Takimoto T., Kim B. Biophysical analysis of influenza A virus RNA promoter at physiological temperatures. J. Biol. Chem. 2011;286(26):22965-22970.

    Not in our library10.1074/jbc.m111.239509

  124. 124.

    Onoguchi K., Yoneyama M., Takemura A., Akira S., Taniguchi T., Namiki H., Fujita T. Viral infections activate types I and III interferon genes through a common mechanism. J. Biol. Chem. 2007;282(10):7576-7581.

    Not in our library10.1074/jbc.m608618200

  125. 125.

    Oshiumi H., Matsumoto M., Hatakeyama S., Seya T. Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-β induction during the early phase of viral infection. J. Biol. Chem. 2009;284(2):807-817.

    Not in our library10.1074/jbc.m804259200

  126. 126.

    Oshiumi H., Miyashita M., Inoue N., Okabe M., Matsumoto M., Seya T. The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. Cell Host Microbe. 2010;8(6):496-509.

    Not in our library10.1016/j.chom.2010.11.008

  127. 127.

    Osterlund P., Strengell M., Sarin L.P., Poranen M.M., Fagerlund R., Melen K., Julkunen I. Incoming influenza A virus evades early host recognition, while influenza B virus induces interferon expression directly upon entry. J. Virol. 2012;86(20):11183-11193.

    Not in our library10.1128/jvi.01050-12

  128. 128.

    Osterlund P.I., Pietila T.E., Veckman V., Kotenko S.V., Julkunen I. IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes. J. Immunol. 2007;179(6):3434-3442.

    Not in our library10.4049/jimmunol.179.6.3434

  129. 129.

    Park C.J., Bae S.H., Lee M.K., Varani G., Choi B.S. Solution structure of the influenza A virus cRNA promoter: implications for differential recognition of viral promoter structures by RNA-dependent RNA polymerase. Nucleic Acids Res. 2003;31(11):2824-2832.

    Not in our library10.1093/nar/gkg387

  130. 130.

    Pavlovic J., Haller O., Staeheli P. Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J. Virol. 1992;66(4):2564-2569.

    Not in our library10.1128/jvi.66.4.2564-2569.1992

  131. 131.

    Perez-Cidoncha M., Killip M.J., Oliveros J.C., Asensio V.J., Fernandez Y., Bengoechea J.A., Randall R.E., Ortin J. An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response. J. Virol. 2014;88(9):4632-4646.

    Not in our library10.1128/jvi.00014-14

  132. 132.

    Pflug A., Guilligay D., Reich S., Cusack S. Structure of influenza A polymerase bound to the viral RNA promoter. Nature. 2014;516(7531):355-360.

    Not in our library10.1038/nature14008

  133. 133.

    Pichlmair A., Schulz O., Tan C.P., Naslund T.I., Liljestrom P., Weber F., Reis e Sousa C. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science. 2006;314(5801):997-1001.

    Not in our library10.1126/science.1132998

  134. 134.

    Rand U., Rinas M., Schwerk J., Nohren G., Linnes M., Kroger A., Flossdorf M., Kaly-Kullai K., Hauser H., Hofer T., Koster M. Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response. Mol. Syst. Biol. 2012;8:584.

    Not in our library10.1038/msb.2012.17

  135. 135.

    Randall R.E., Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 2008;89(Pt 1):1-47.

    Not in our library10.1099/vir.0.83391-0

  136. 136.

    Rehwinkel J., Tan C.P., Goubau D., Schulz O., Pichlmair A., Bier K., Robb N., Vreede F., Barclay W., Fodor E., Reis e Sousa C. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell. 2010;140(3):397-408.

    Not in our library10.1016/j.cell.2010.01.020

  137. 137.

    Resa-Infante P., Jorba N., Coloma R., Ortin J. The influenza virus RNA synthesis machine: advances in its structure and function. RNA Biol. 2011;8(2):207-215.

    Not in our library10.4161/rna.8.2.14513

  138. 138.

    Resa-Infante P., Recuero-Checa M.A., Zamarreno N., Llorca O., Ortin J. Structural and functional characterization of an influenza virus RNA polymerase–genomic RNA complex. J. Virol. 2010;84(20):10477-10487.

    Not in our library10.1128/jvi.01115-10

  139. 139.

    Robertson J.S. 5′ and 3′ terminal nucleotide sequences of the RNA genome segments of influenza virus. Nucleic Acids Res. 1979;6(12):3745-3757.

    Not in our library10.1093/nar/6.12.3745

  140. 140.
    In Vivo Ligands of MDA5 and RIG-I in Measles Virus-Infected Cells · 2014
    No notice
  141. 141.

    Saira K., Lin X., DePasse J.V., Halpin R., Twaddle A., Stockwell T., Angus B., Cozzi-Lepri A., Delfino M., Dugan V., Dwyer D.E., Freiberg M., Horban A., Losso M., Lynfield R., Wentworth D.N., Holmes E.C., Davey R., Wentworth D.E., Ghedin E. Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus. J. Virol. 2013;87(14):8064-8074.

    Not in our library10.1128/jvi.00240-13

  142. 142.

    Saito T., Hirai R., Loo Y.M., Owen D., Johnson C.L., Sinha S.C., Akira S., Fujita T., Gale M. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl. Acad. Sci. U. S. A. 2007;104(2):582-587.

    Not in our library10.1073/pnas.0606699104

  143. 143.

    Saito T., Owen D.M., Jiang F., Marcotrigiano J., Gale M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008;454(7203):523-527.

    Not in our library10.1038/nature07106

  144. 144.

    Satoh T., Kato H., Kumagai Y., Yoneyama M., Sato S., Matsushita K., Tsujimura T., Fujita T., Akira S., Takeuchi O. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl. Acad. Sci. U. S. A. 2010;107(4):1512-1517.

    Not in our library10.1073/pnas.0912986107

  145. 145.

    Satterly N., Tsai P.L., van Deursen J., Nussenzveig D.R., Wang Y., Faria P.A., Levay A., Levy D.E., Fontoura B.M. Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc. Natl. Acad. Sci. U. S. A. 2007;104(6):1853-1858.

    Not in our library10.1073/pnas.0610977104

  146. 146.

    Schlee M., Roth A., Hornung V., Hagmann C.A., Wimmenauer V., Barchet W., Coch C., Janke M., Mihailovic A., Wardle G., Juranek S., Kato H., Kawai T., Poeck H., Fitzgerald K.A., Takeuchi O., Akira S., Tuschl T., Latz E., Ludwig J., Hartmann G. Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity. 2009;31(1):25-34.

    Not in our library10.1016/j.immuni.2009.05.008

  147. 147.

    Schmidt A., Schwerd T., Hamm W., Hellmuth J.C., Cui S., Wenzel M., Hoffmann F.S., Michallet M.C., Besch R., Hopfner K.P., Endres S., Rothenfusser S. 5′-Triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc. Natl. Acad. Sci. U. S. A. 2009;106(29):12067-12072.

    Not in our library10.1073/pnas.0900971106

  148. 148.

    Scott P.D., Meng B., Marriott A.C., Easton A.J., Dimmock N.J. Defective interfering influenza A virus protects in vivo against disease caused by a heterologous influenza B virus. J. Gen. Virol. 2011;92(Pt. 9):2122-2132.

    Not in our library10.1099/vir.0.034132-0

  149. 149.

    Shapiro G.I., Krug R.M. Influenza virus RNA replication in vitro: synthesis of viral template RNAs and virion RNAs in the absence of an added primer. J. Virol. 1988;62(7):2285-2290.

    Not in our library10.1128/jvi.62.7.2285-2290.1988

  150. 150.

    Shaw M.L., Palese P., Knipe D.M., Howley P.M. Orthomyxoviridae. Fields Virology. 2013;1151-1185.

    Not in our library

  151. 151.

    Shingai M., Ebihara T., Begum N.A., Kato A., Honma T., Matsumoto K., Saito H., Ogura H., Matsumoto M., Seya T. Differential type I IFN-inducing abilities of wild-type versus vaccine strains of measles virus. J. Immunol. 2007;179(9):6123-6133.

    Not in our library10.4049/jimmunol.179.9.6123

  152. 152.
    IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo · 2008
    No notice
  153. 153.

    Steidle S., Martinez-Sobrido L., Mordstein M., Lienenklaus S., Garcia-Sastre A., Staheli P., Kochs G. Glycine 184 in nonstructural protein NS1 determines the virulence of influenza A virus strain PR8 without affecting the host interferon response. J. Virol. 2010;84(24):12761-12770.

    Not in our library10.1128/jvi.00701-10

  154. 154.

    Strahle L., Garcin D., Kolakofsky D. Sendai virus defective-interfering genomes and the activation of interferon-beta. Virology. 2006;351(1):101-111.

    Not in our library10.1016/j.virol.2006.03.022

  155. 155.

    Strahle L., Marq J.B., Brini A., Hausmann S., Kolakofsky D., Garcin D. Activation of the beta interferon promoter by unnatural Sendai virus infection requires RIG-I and is inhibited by viral C proteins. J. Virol. 2007;81(22):12227-12237.

    Not in our library10.1128/jvi.01300-07

  156. 156.

    Sun Q., Sun L., Liu H.H., Chen X., Seth R.B., Forman J., Chen Z.J. The specific and essential role of MAVS in antiviral innate immune responses. Immunity. 2006;24(5):633-642.

    Not in our library10.1016/j.immuni.2006.04.004

  157. 157.

    Takahasi K., Yoneyama M., Nishihori T., Hirai R., Kumeta H., Narita R., Gale M., Inagaki F., Fujita T. Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol. Cell. 2008;29(4):428-440.

    Not in our library10.1016/j.molcel.2007.11.028

  158. 158.

    Tan K.S., Olfat F., Phoon M.C., Hsu J.P., Howe J.L., Seet J.E., Chin K.C., Chow V.T. In vivo and in vitro studies on the antiviral activities of viperin against influenza H1N1 virus infection. J. Gen. Virol. 2012;93(Pt 6):1269-1277.

    Not in our library10.1099/vir.0.040824-0

  159. 159.
    Defective Viral Genomes Arising In Vivo Provide Critical Danger Signals for the Triggering of Lung Antiviral Immunity · 2013
    No notice
  160. 160.

    Tiley L.S., Hagen M., Matthews J.T., Krystal M. Sequence-specific binding of the influenza virus RNA polymerase to sequences located at the 5′ ends of the viral RNAs. J. Virol. 1994;68(8):5108-5116.

    Not in our library10.1128/jvi.68.8.5108-5116.1994

  161. 161.

    Tomescu A.I., Robb N.C., Hengrung N., Fodor E., Kapanidis A.N. Single-molecule FRET reveals a corkscrew RNA structure for the polymerase-bound influenza virus promoter. Proc. Natl. Acad. Sci. U. S. A. 2014;111(32):E3335-E3342.

    Not in our library10.1073/pnas.1406056111

  162. 162.

    Turan K., Mibayashi M., Sugiyama K., Saito S., Numajiri A., Nagata K. Nuclear MxA proteins form a complex with influenza virus NP and inhibit the transcription of the engineered influenza virus genome. Nucleic Acids Res. 2004;32(2):643-652.

    Not in our library10.1093/nar/gkh192

  163. 163.

    Turrell L., Lyall J.W., Tiley L.S., Fodor E., Vreede F.T. The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes. Nat. Commun. 2013;4:1591.

    Not in our library10.1038/ncomms2589

  164. 164.

    Uzri D., Gehrke L. Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities. J. Virol. 2009;83(9):4174-4184.

    Not in our library10.1128/jvi.02449-08

  165. 165.
    The Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon at the Level of the MAVS Adaptor Protein · 2011
    No notice
  166. 166.

    Von Magnus P. Propagation of the PR8 strain of influenza A virus in chick embryos. II. The formation of incomplete virus following inoculation of large doses of seed virus. Acta Pathol. Microbiol. Scand. 1951;28(3):278-293.

    Not in our library10.1111/j.1699-0463.1951.tb03693.x

  167. 167.

    Von Magnus P. Propagation of the PR8 strain of influenza A virus in chick embryos. III. Properties of the incomplete virus produced in serial passages of undiluted virus. Acta Pathol. Microbiol. Scand. 1951;29(2):157-181.

    Not in our library10.1111/j.1699-0463.1951.tb00114.x

  168. 168.

    Vreede F.T., Chan A.Y., Sharps J., Fodor E. Mechanisms and functional implications of the degradation of host RNA polymerase II in influenza virus infected cells. Virology. 2010;396(1):125-134.

    Not in our library10.1016/j.virol.2009.10.003

  169. 169.

    Vreede F.T., Jung T.E., Brownlee G.G. Model suggesting that replication of influenza virus is regulated by stabilization of replicative intermediates. J. Virol. 2004;78(17):9568-9572.

    Not in our library10.1128/jvi.78.17.9568-9572.2004

  170. 170.

    Vreede F.T., Ng A.K., Shaw P.C., Fodor E. Stabilization of influenza virus replication intermediates is dependent on the RNA-binding but not the homo-oligomerization activity of the viral nucleoprotein. J. Virol. 2011;85(22):12073-12078.

    Not in our library10.1128/jvi.00695-11

  171. 171.

    Wang J., Oberley-Deegan R., Wang S., Nikrad M., Funk C.J., Hartshorn K.L., Mason R.J. Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-lambda 1) in response to influenza A infection. J. Immunol. 2009;182(3):1296-1304.

    Not in our library10.4049/jimmunol.182.3.1296

  172. 172.

    Wang X., Hinson E.R., Cresswell P. The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe. 2007;2(2):96-105.

    Not in our library10.1016/j.chom.2007.06.009

  173. 173.

    Wang X., Li M., Zheng H., Muster T., Palese P., Beg A.A., Garcia-Sastre A. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J. Virol. 2000;74(24):11566-11573.

    Not in our library10.1128/jvi.74.24.11566-11573.2000

  174. 174.

    Wang Y., Ludwig J., Schuberth C., Goldeck M., Schlee M., Li H., Juranek S., Sheng G., Micura R., Tuschl T., Hartmann G., Patel D.J. Structural and functional insights into 5′-ppp RNA pattern recognition by the innate immune receptor RIG-I. Nat. Struct. Mol. Biol. 2010;17(7):781-787.

    Not in our library10.1038/nsmb.1863

  175. 175.

    Weber F., Wagner V., Rasmussen S.B., Hartmann R., Paludan S.R. Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J. Virol. 2006;80(10):5059-5064.

    Not in our library10.1128/jvi.80.10.5059-5064.2006

  176. 176.

    Weber M., Gawanbacht A., Habjan M., Rang A., Borner C., Schmidt A.M., Veitinger S., Jacob R., Devignot S., Kochs G., Garcia-Sastre A., Weber F. Incoming RNA virus nucleocapsids containing a 5′-triphosphorylated genome activate RIG-I and antiviral signaling. Cell Host Microbe. 2013;13(3):336-346.

    Not in our library10.1016/j.chom.2013.01.012

  177. 177.

    Wisskirchen C., Ludersdorfer T.H., Muller D.A., Moritz E., Pavlovic J. The cellular RNA helicase UAP56 is required for prevention of double-stranded RNA formation during influenza A virus infection. J. Virol. 2011;85(17):8646-8655.

    Not in our library10.1128/jvi.02559-10

  178. 178.

    Xiao H., Killip M.J., Staeheli P., Randall R.E., Jackson D. The human interferon-induced MxA protein inhibits early stages of influenza A virus infection by retaining the incoming viral genome in the cytoplasm. J. Virol. 2013;87(23):13053-13058.

    Not in our library10.1128/jvi.02220-13

  179. 179.

    Ye Q., Krug R.M., Tao Y.J. The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature. 2006;444(7122):1078-1082.

    Not in our library10.1038/nature05379

  180. 180.

    Yoneyama M., Kikuchi M., Natsukawa T., Shinobu N., Imaizumi T., Miyagishi M., Taira K., Akira S., Fujita T. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 2004;5(7):730-737.

    Not in our library10.1038/ni1087

  181. 181.

    York A., Hengrung N., Vreede F.T., Huiskonen J.T., Fodor E. Isolation and characterization of the positive-sense replicative intermediate of a negative-strand RNA virus. Proc. Natl. Acad. Sci. U. S. A. 2013;110(45):E4238-E4245.

    Not in our library10.1073/pnas.1315068110

  182. 182.

    Zeng W., Sun L., Jiang X., Chen X., Hou F., Adhikari A., Xu M., Chen Z.J. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell. 2010;141(2):315-330.

    Not in our library10.1016/j.cell.2010.03.029

  183. 183.
    Stochastic Expression of the Interferon-β Gene · 2012
    No notice
  184. 184.

    Zimmermann P., Manz B., Haller O., Schwemmle M., Kochs G. The viral nucleoprotein determines Mx sensitivity of influenza A viruses. J. Virol. 2011;85(16):8133-8140.

    Not in our library10.1128/jvi.00712-11

Cited by papers we hold 4

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.