IFI16 functions as an antiviral factor during influenza virus infection by binding viral RNA and enhancing the RIG-I signaling
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ABSTRACT:
ORGANISM(S): Influenza A virus Homo sapiens
PROVIDER: GSE158123 | GEO | 2020/09/17
REPOSITORIES: GEO
Similar Datasets
Project description:RIG-I is thought to be the most important sensor of influenza virus infection and plays critical roles in the recognition of cytoplasmic dsRNA and activation of type I IFNs and initiates the innate antiviral immune responses. How the binding of viral RNA to and activation of RIG-I are regulated remains enigmatic. Here, by an affinity proteomics approach with viral RNA as the bait, we found that IFI16, previously identified as a DNA sensor, was significantly induced both in vitro and in vivo during influenza virus infection. Using an IFI16 knockout cells and p204-deficient mice model, we demonstrated that IFI16 enhanced RIG-I-mediated production of type I IFNs and thereby inhibited viral replication during influenza virus infection. Furthermore, we showed that IFI16 regulated the RIG-I signaling by enhancing its transcriptional expression through recruitment of RNA Pol II to the RIG-I promoter. We also verified that IFI16 directly interacted with both viral RNA by HINa domain and associated with RIG-I through its PYRIN domain as well as promoted influenza virus-induced K63-linked polyubiquitination of RIG-I. In addition, we found that IFI16 lost its ability to inhibit viral replication in the absence of RIG-I in virus-infected cells. These results indicate that IFI16 is a key regulator of the RIG-I signaling during antiviral innate immune responses, which highlights a novel mechanism of IFI16 in IAV and other RNA viruses infection, expands our knowledge in antiviral innate immunity, and suggests its possible use as a new strategies to manipulate antiviral responses.
2020-09-17 | GSE158122 | GEO
Project description:RIG-I is thought to be the most important sensor of influenza virus infection and plays critical roles in the recognition of cytoplasmic dsRNA and activation of type I IFNs and initiates the innate antiviral immune responses. How the binding of viral RNA to and activation of RIG-I are regulated remains enigmatic. Here, by an affinity proteomics approach with viral RNA as the bait, we found that IFI16, previously identified as a DNA sensor, was significantly induced both in vitro and in vivo during influenza virus infection. Using an IFI16 knockout cells and p204-deficient mice model, we demonstrated that IFI16 enhanced RIG-I-mediated production of type I IFNs and thereby inhibited viral replication during influenza virus infection. Furthermore, we showed that IFI16 regulated the RIG-I signaling by enhancing its transcriptional expression through recruitment of RNA Pol II to the RIG-I promoter. We also verified that IFI16 directly interacted with both viral RNA by HINa domain and associated with RIG-I through its PYRIN domain as well as promoted influenza virus-induced K63-linked polyubiquitination of RIG-I. In addition, we found that IFI16 lost its ability to inhibit viral replication in the absence of RIG-I in virus-infected cells. These results indicate that IFI16 is a key regulator of the RIG-I signaling during antiviral innate immune responses, which highlights a novel mechanism of IFI16 in IAV and other RNA viruses infection, expands our knowledge in antiviral innate immunity, and suggests its possible use as a new strategies to manipulate antiviral responses.
2020-09-09 | GSE157609 | GEO
Project description:IFI16 functions as an antiviral factor during influenza virus infection by binding viral RNA and enhancing the RIG-I signaling
| PRJNA664043 | ENA
Project description:IFI16 functions as an antiviral factor during influenza virus infection by binding viral RNA and enhancing the RIG-I signaling (RNA-seq)
| PRJNA662224 | ENA
Project description:IFI16 functions as an antiviral factor during influenza virus infection by binding viral RNA and enhancing the RIG-I signaling (RIP-seq)
| PRJNA664055 | ENA
Project description:The interaction of viral nucleic acid with protein factors is a crucial process for initiating viral polymerase-mediated viral genome replication while activating pattern recognition receptor (PRR)-mediated innate immune responses. It has previously been reported that a hydrolysate of Ge-132, 3-(trihydroxygermyl) propanoic acid (THGP), shows a modulatory effect on microbial infections, inflammation, and immune responses. However, the detailed mechanism by which THGP can modify these processes during viral infections remained unknown. Here, we show that THGP can specifically downregulate type I interferon (IFN) production in response to stimulation with a cytosolic RNA sensor RIG-I ligand 5'-triphosphate RNA (3pRNA) but not double-stranded RNA, DNA, or lipopolysaccharide. Consistently, treatment with THGP resulted in the dose-dependent suppression of type I IFN induction upon infections with influenza virus (IAV) and vesicular stomatitis virus, which are known to be mainly sensed by RIG-I. Mechanistically, THGP directly binds to the 5'-triphosphate moiety of viral RNA and competes with RIG-I-mediated recognition. Furthermore, we found that THGP can directly counteract the replication of IAV but not EMCV (encephalitismyocarditis virus), by inhibiting the interaction of viral polymerase with RNA genome. Finally, IAV RNA levels were significantly reduced in the lung tissues of THGP-treated mice when compared with untreated mice. These results suggest a possible therapeutic implication of THGP and show direct antiviral action, together with the suppressive activity of innate inflammation.
| S-EPMC8473027 | biostudies-literature
Project description:RIG-I functions as a virus sensor that induces a cellular antiviral response. Although it has been investigated in other species, there have been no further studies to date on canine RIG-I against canine influenza virus (CIV). In the present study, we cloned the RIG-I gene of beagle dogs and characterized its expression, subcellular localization, antiviral response, and interactions with CIV proteins. RIG-I was highly expressed and mainly localized in the cytoplasm, with low levels detected in the nucleus. The results revealed that overexpression of the CARD domain of RIG-I and knockdown of RIG-I showed its ability to activate the RLR pathway and induced the expression of downstream interferon-stimulated genes. Moreover, overexpression of canine RIG-I suppressed the replication of CIV. The association between RIG-I and CIV was evaluated with the luciferase assay and by indirect immunofluorescence and bimolecular fluorescence complementation analyses. The results showed that CIV nonstructural protein 1 (NS1) can strongly suppress the RIG-I-mediated innate immune response, and the novel interactions between CIV matrix proteins (M1 and M2) and canine RIG-I were disclosed. These findings provide a basis for investigating the antiviral mechanism of canine RIG-I against CIV, which can lead to effective strategies for preventing CIV infection in dogs.
| S-EPMC8540569 | biostudies-literature
Project description:The E3 ubiquitin ligase TRIM25 is a key factor in the innate immune response to RNA viruses. TRIM25 has been shown to play a role in the retinoic-acid-inducible gene-1 (RIG-I) pathway, which triggers expression of type 1 interferons upon viral infection. We and others have shown that TRIM25 is an RNA-binding protein; however, the role of TRIM25 RNA-binding in the innate immune response to RNA viruses is unclear. Here, we demonstrate that influenza A virus (IAV A/PR/8/34_NS1(R38A/K41A)) infection is inhibited by TRIM25. Surprisingly, previously identified RNA-binding deficient mutant TRIM25ΔRBD and E3 ubiquitin ligase mutant TRIM25ΔRING, which lack E3 ubiquitin ligase activity, still inhibited IAV replication. Furthermore, we show that in human-derived cultured cells, activation of the RIG-I/interferon type 1 pathway mediated by either an IAV-derived 5'-triphosphate RNA or by IAV itself does not require TRIM25 activity. Additionally, we present new evidence that instead of TRIM25 directly inhibiting IAV transcription it binds and destabilizes IAV mRNAs. Finally, we show that direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. In summary, our results uncover a potential mechanism that TRIM25 uses to inhibit IAV infection and regulate RNA metabolism.
| S-EPMC9262604 | biostudies-literature
Project description:RationaleA family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response, which may have therapeutic potential. We investigated immune response modulation by SLR10. We addressed whether RIG-I pathway activation with SLR10 leads to protection of nonsmoking (NS) and cigarette smoke (CS)-exposed mice after influenza A virus (IAV) infection.MethodsMice were given 25 µg of SLR10 1 day before IAV infection. We compared the survival rates and host immune responses of NS and CS-exposed mice following challenge with IAV.ResultsSLR10 significantly decreased weight loss and increased survival rates in both NS and CS-exposed mice during IAV infection. SLR10 administration repaired the impaired proinflammatory response in CS-exposed mice without causing more lung injury in NS mice as assessed by physiologic measurements. Although histopathologic study revealed that SLR10 administration was likely to result in higher pathological scores than untreated groups in both NS and CS mice, this change was not enough to increase lung injury evaluated by lung-to-body weight ratio. Both qRT-PCR on lung tissues and multiplex immunoassay on bronchoalveolar lavage fluids (BALFs) showed that most IFNs and proinflammatory cytokines were expressed at lower levels in SLR10-treated NS mice than control-treaded NS mice at day 5 post infection (p.i.). Remarkably, proinflammatory cytokines IL-6, IL-12, and GM-CSF were increased in CS-exposed mice by SLR10 at day 5 p.i. Significantly, SLR10 elevated the ratio of the two chemokines (CXCL9 and CCL17) in BALFs, suggesting macrophages were polarized to classically activated (M1) status. In vitro testing also found that SLR10 not only stimulated human alveolar macrophage polarization to an M1 phenotype, but also reversed cigarette smoke extract (CSE)-induced M2 to M1 polarization.ConclusionsOur data show that SLR10 administration in mice is protective for both NS and CS-exposed IAV-infected mice. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection. The protective effects by SLR10 may be a promising intervention for therapy for infections with viruses, particularly those with CS-enhanced susceptibility to adverse outcomes.
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Project description:Avian influenza viruses (AIVs) cause major economic losses to the global poultry industry. Many host factors have been identified that act as regulators of the inflammatory response and virus replication in influenza A virus (IAV) infected cells including nucleotide-binding oligomerization domain (NOD) like receptor (NLR) family proteins. Evidence is emerging that NLRC5, the largest NLR member, is a regulator of host immune responses against invading pathogens including viruses; however, its role in the avian immune system and AIV pathogenesis has not been fully explored. In this study, we found that NLRC5 is activated by a range of low and highly pathogenic AIVs in primary chicken lung cells and a chicken macrophage cell line. Further, siRNA mediated NLRC5 knockdown in chicken macrophages resulted in a significant reduction in AIV replication which was associated with the upregulation of genes associated with activated NFκB signaling pathway. The knockdown of NLRC5 enhanced the expression of genes known to be associated with viral defense and decreased innate cytokine gene expression following AIV infection. Overall, our investigation strongly suggests that NLRC5 is a pro-viral factor during IAV infection in chicken and may contribute to pathogenesis through innate cytokine regulation. Further studies are warranted to investigate the IAV protein(s) that may regulate activation of NLRC5.
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