Regulation of Innate Immunity by the Flaviviridae

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.