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Chapter 17 : Suppression of Innate Immunity by Orthomyxoviruses
Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology
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This chapter discusses how influenza virus infection triggers the production of type I interferon (IFNs), the signaling cascades that the cytokines stimulate to establish a protective antiviral response, and the mechanisms that orthomyxoviruses employ to circumvent the host's innate immunity. Orthomyxoviruses employ several strategies to circumvent the host’s innate and adaptive immune responses; the effectiveness by which the viruses apply the strategies contributes to the clinical outcome of virus infections. For influenza A viruses, the viral hemagglutinin and neuraminidase glycoproteins substantially contribute to the pathogenesis of influenza virus infections. An important consideration in the induction of IFN by influenza virus relates to the actual nature of the viral inducer recognized by the cellular sensors. IFN-inducible Mx homologues belong to the dynamin-like family of GTPases that are normally associated with intracellular vesicle trafficking and organelle homeostasis. Promyelocytic leukemia (PML) protein (also known as TRIM19) is an additional IFN-inducible protein that accumulates within nuclear structures that have been referred to as nuclear dot 10 (ND10) or nuclear bodies. The studies discussed in the chapter have concisely described the mechanisms by which, in the absence of the nonstructural protein 1 (NS1), the host detects virus replication, stimulates expression of the IFN-β gene and IFN-stimulated genes (ISGs), and establishes an antiviral state that controls replication of and pathogenicity resulting from infection by orthomyxoviruses.
Key Concept Ranking
- Influenza A virus Subtype H5N1
Regulation of innate and adaptive immune responses by the influenza A virus NS1 protein. Mutational analyses of the influenza A virus NS1 protein have identified several domains that control its intracellular localization or are essential for its regulation of general gene expression and antiviral immunity. The diverse cellular processes that are regulated by the NS1 protein and the molecules targeted within each process are indicated. The schematic depicts a hypothetical NS1 protein of 230 amino acids. Amino acid positions are identified for the indicated functional domains.
Regulation of IFN-β and IFN-mediated gene induction during influenza A virus infection. The influenza A virus NS1 protein utilizes several strategies to regulate the induction of type I IFNs, including (i) binding to and sequestration of dsRNA and ssRNA from the cellular sensor, RIG-I; (ii) interaction with RIG-I; and (iii) binding to components involved in mRNA processing, export, and translation. As a consequence of the first two strategies, the NS1 protein blocks the activation of the transcription factors IRF3, NF-κB, and ATF-2/c-Jun, thus preventing the formation of the IFN-β enhanceosome. The third strategy employed by the NS1 protein coupled with the cap-snatching function of the viral polymerase complex contributes to the general inhibition of IFN-β and IFN-induced gene expression.