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Identification of avian RIG-I responsive genes during influenza infection.

ABSTRACT: Ducks can survive infection with highly pathogenic avian influenza viruses that are lethal to chickens. We showed that the influenza detector, RIG-I can initiate antiviral responses in ducks, but this gene is absent in chickens. We can reconstitute this pathway by transfecting chicken DF-1 embryonic fibroblast cells with duck RIG-I, which augments their antiviral response to influenza and decreases viral titer. However, the genes downstream of duck RIG-I that mediate this antiviral response to influenza are not known. Using microarrays, we compared the transcriptional profile of chicken embryonic fibroblasts transfected with duck RIG-I or empty vector, and infected with low or highly pathogenic avian influenza viruses. Transfected duck RIG-I expressed in chicken cells was associated with the marked induction of many antiviral innate immune genes upon infection with both viruses. We used real-time PCR to confirm upregulation of a subset of these antiviral genes including MX1, PKR, IFIT5, OASL, IFNB, and downregulation of the influenza matrix gene. These results provide some insight into the genes induced by duck RIG-I upon influenza infection, and provide evidence that duck RIG-I can function to elicit an interferon-driven, antiviral response against influenza in chicken embryonic fibroblasts.

SUBMITTER: Barber MR

PROVIDER: S-EPMC3565471 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Identification of avian RIG-I responsive genes during influenza infection.

Barber Megan R W MR Aldridge Jerry R JR Fleming-Canepa Ximena X Wang Yong-Dong YD Webster Robert G RG Magor Katharine E KE

Molecular immunology 20121204 1

Ducks can survive infection with highly pathogenic avian influenza viruses that are lethal to chickens. We showed that the influenza detector, RIG-I can initiate antiviral responses in ducks, but this gene is absent in chickens. We can reconstitute this pathway by transfecting chicken DF-1 embryonic fibroblast cells with duck RIG-I, which augments their antiviral response to influenza and decreases viral titer. However, the genes downstream of duck RIG-I that mediate this antiviral response to i ...[more]

PMID: 23220072

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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.

Dataset Information

Identification of avian RIG-I responsive genes during influenza infection.

Publications

Identification of avian RIG-I responsive genes during influenza infection.

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