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Chapter 20 : Regulation of Innate Immunity by the Flaviviridae
Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology
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This chapter provides an overview of Flaviviridae and their regulation of host-cell innate immune defenses. The viruses that comprise the Flaviviridae family are small enveloped, single-stranded, positive-sense RNA viruses. The Flaviviridae are divided into three genera of more closely related viruses: Flavivirus, Pestivirus, and Hepacivirus. Hepatitis C virus (HCV) is now the most common cause of liver failure and liver transplantation in the United States and Europe. The ability to sense an invading pathogen is critical to the cell’s ability to respond in an appropriate manner to clear the infection. The cell utilizes a group of proteins known as pathogen recognition receptors (PRRs) to detect the presence of pathogen-associated molecular patterns (PAMPs) within products of viral replication. It is likely that RIG-I primarily detects motifs within the genomes of Japanese encephalitis virus (JEV), dengue virus (DV), and West Nile virus (WNV), as it does with HCV, since Flavivirus genomes are capped and therefore do not present naked 5' ppp motifs as PAMPs. Examination of interferon (IFN) signaling in infected cells has revealed strategies by which Flaviviridae members attenuate IFN-a/β receptor signaling actions, thus limiting the downstream expression of ISGs that otherwise control virus replication and spread. The Flaviviridae represent major pathogens of public health, agriculture, and environmental importance. Molecular studies have revealed common and unique mechanisms by which members of the different Flaviviridae genera evade host innate immunity and IFN actions that would otherwise limit infection.
Genome and protein-coding organization of the Flaviviridae genera. The positions of the nontranslated region (NTR) and the polyprotein encoding the structural and non-structural (NS) proteins are shown. Cap denotes the 5′ cap present on Flavivirus genome RNA; IRES denotes the internal ribosome entry site found within the Hepacivirus and Pestivirus genome RNA. The positions of the mature viral proteins within each viral polyprotein are indicated. The structural proteins are abbreviated as follows: C, capsid; prM/M, membrane; E, envelope; E1, envelope protein 1; E2, envelope protein 2; ERNS, envelope. The NS proteins are designated 1 to 5 with A and B subtypes, as shown.
PRR signaling and viral control of the innate immune response to Flaviviridae infection. Viral RNA recognition by the TLR3 and RIG-I/MDA-5 pathways are shown. Recognition and binding of viral RNA products by TLRs, RIG-I, or MDA-5 induces downstream signaling of IRF3 and NF-κB activation, leading to the expression of a wide range of genes, including the production and secretion of IFN-β. The sites of regulation by BVDV Npro and HCV NS3/4A proteins are indicated. Ubq-Ubq, protein modification by virus-induced ubiquitin chain conjugation; P, protein phosphorylation; NEMO, NF-κB essential modulator.
Regulation of the Jak-Stat pathway during Flaviviridae infection. The two chains of the IFN-α/β receptor are shown associated with Tyk2 or Jak1. IFN binding to the receptor triggers the phosphorylation of receptor-associated Stat1 and Stat2, which form heterodimers that translocate to the cell nucleus for interaction with IRF9. The trimeric complex of Stat1, Stat2, and IRF9 binds to the ISRE of target genes to induce ISG expression. ISG products function to control virus replication and cell-to-cell virus spread, and have a major impact on tissue tropism. Sites of Jak-Stat pathway regulation by HCV core, NS5A, and E2 proteins are indicated. Control points imposed by WNV, DV, TBE/Langat virus, and JEV NS proteins are also shown. pY, protein tyrosine phosphorylation.