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RNA-dependent RNA polymerase sequence specificities of capsnatching viruses are tailored to aid viral replication

ABSTRACT: Influenza A virus (IAV) is a major respiratory pathogen that causes severe illness and mortality worldwide. IAV critically depends on host factors for multiple functions that are not encoded by the viral genome. Notably, the IAV RNA-dependent RNA polymerase (RdRP) complex lacks intrinsic 7-methylguanosine (m7G) capping activity and instead “snatches” the 5’m7G caps and the adjacent 10-15nts of host transcripts to prime viral mRNA production, allowing viral transcripts to be recognized by the host translation machinery. We developed a new approach to simultaneously assay the 5’ ends of host and viral transcripts in infected cells and identify the host capsnatch origins for viral mRNAs. We used this technique to study the progression of IAV infection in nuclear and cytoplasmic compartiments and determined that the RdRP complex has specific sequence preferences that results in preferential capsnatching and avoidance of sub-populations of host RNAs, which can be reverted by the addition of a cap-snatch inhibitor. Notably, genes avoided by CapSnatch Seq have biological functions enriched for mRNA processing, translation, and viral replication. This selectivity and functional enrichment of avoided genes is conserved among capsnatching viruses including Influenza B Virus and Lymphocytic Choriomeningitis Virus, despite differences in RdRP domains and subcellular locations of RNA substrates. This suggests that this preference convergently arose as a viral strategy to allow cap-snatching viruses to avoid targeting genes necessary for its own replication.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85474 | GEO | 2017/08/09

SECONDARY ACCESSION(S): PRJNA338988

REPOSITORIES: GEO

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Project description:Influenza A virus (IAV) infection causes acute respiratory disease with potential severe and deadly complications. Viral pathogenesis is not only due to the direct cytopathic effect of viral infections but also to the exacerbated host inflammatory responses. Influenza viral infection can activate various host signaling pathways that function to activate or inhibit viral replication. Our previous studies have shown that a receptor tyrosine kinase TrkA plays an important role in the replication of influenza viruses in vitro, but its biological roles and functional mechanisms in influenza viral infection have not been characterized. Here we show that IAV infection strongly activates TrkA in vitro and in vivo. Using a chemical-genetic approach to specifically control TrkA kinase activity through a small molecule compound 1NMPP1 in a TrkA knock-in (TrkA KI) mouse model, we show that 1NMPP1-mediated TrkA inhibition completely protected mice from a lethal IAV infection by significantly reducing viral loads and lung inflammation. Using primary lung cells isolated from the TrkA KI mice, we show that specific TrkA inhibition reduced viral RNA synthesis in airway epithelial cells (AECs) but not in alveolar macrophages (AMs). Transcriptomic analysis confirmed the cell-type-specific role of TrkA in viral RNA synthesis, and identified distinct gene expression patterns under the TrkA regulation in IAV-infected AECs and AMs. Among the TrkA-activated targets are various proinflammatory cytokines and chemokines such as IL6, IL-1, IFNs, CCL-5, and CXCL9, supporting the role of TrkA in mediating lung inflammation. Indeed, TrkA inhibitor 1NMPP1 administered after the peak of IAV replication, though had no effect on viral load, was able to decrease lung inflammation and provide partial protection in mice. Taken together, our results have demonstrated for the first time an important biological role of TrkA signaling in IAV infection, identified its cell-type-specific contribution to viral replication, and revealed its functional mechanism in virus-induced lung inflammation. This study suggests TrkA as a novel host target for therapeutics against influenza viral disease.

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RNA-dependent RNA polymerase sequence specificities of capsnatching viruses are tailored to aid viral replication

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