The virus/host interactions that control the transition from acute to chronic virus infection are not well understood. Hepatitis C virus (HCV) is a model RNA virus of chronic infection and is a contemporary public health problem. This application continues our focus on defining the molecular mechanisms of hepatic innate immunity that impart acute to chronic HCV infection outcome. We have shown that retinoic acid inducible gene-I (RIG-I) initiates the hepatic innate immune response upon recognition and binding of the pathogen associated molecular pattern (PAMP) consisting of 5' triphosphate and the poly-uridine/cytosine (pU/UC) motif within the HCV RNA. During acute infection this recognition of the transmission/founder (T/F) viral genome by RIG-I results in its modification and activation to bind the MAVS adaptor protein on mitochondria-associated membranes (MAM) and signal hepatic innate immune defenses that restrict infection. Our preliminary studies now reveal that T/F genomes from patients exhibit remarkable variation within their pU/UC motif, and that this variation imparts differential recognition and binding by RIG-I that allows escape from non-self-recognition. Moreover, we have found that signaling by RIG-I is dependent on formation of a RIG-I translocon protein complex that facilitates RIG-I cytosol-to-membrane translocation for MAVS interaction and signaling on the MAM. Our studies now reveal that these activities are governed by the reversible acteylation of RIG-I, and that this process is likely controlled through the HDAC6 protein as a RIG-I cofactor of innate immunity. We show that HCV evades hepatic innate immunity via MAM targeting by the NS3/4A viral protease to cleave MAVS and disrupt RIG-I signaling, thereby facilitating chronic infection, and this action is dependent on stable NS3/4A- MAVS interaction on the MAM. Disruption of this interaction restores innate immunity to prevent acute to chronic HCV transition. We hypothesize that regulation of the RIG-I pathway and hepatic innate immunity are major determinants controlling the acute to chronic transition of HCV infection. We will therefore conduct studies to: 1) Define the RIG-I/PAMP interactions of pathogen recognition and differential innate immune signaling from T/F genomes during acute HCV infection; 2) Determine the role of RIG-I acetylation in translocon assembly and function; 3) Identify the NS3/4A/MAVS interface that mediates interaction to control the RIG-I pathway.
Liver disease from microbial infection is a major public health concern. Hepatitis C virus (HCV) infects the liver to cause liver disease, liver cancer, and death. Our studies will define the virus and host components that control HCV infection outcome and liver disease.
|Hemann, Emily A; Gale Jr, Michael; Savan, Ram (2017) Interferon Lambda Genetics and Biology in Regulation of Viral Control. Front Immunol 8:1707|
|Gorman, Jacquelyn A; Hundhausen, Christian; Errett, John S et al. (2017) The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol 18:744-752|
|Giugliano, Silvia; Petroff, Margaret G; Warren, Bryce D et al. (2017) Correction: Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission. J Immunol 198:972|
|Jarret, Abigail; McFarland, Adelle P; Horner, Stacy M et al. (2016) Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat Med 22:1475-1481|
|Liu, Helene Minyi; Jiang, Fuguo; Loo, Yueh Ming et al. (2016) Regulation of Retinoic Acid Inducible Gene-I (RIG-I) Activation by the Histone Deacetylase 6. EBioMedicine 9:195-206|
|Neufeldt, Christopher J; Joyce, Michael A; Van Buuren, Nicholas et al. (2016) The Hepatitis C Virus-Induced Membranous Web and Associated Nuclear Transport Machinery Limit Access of Pattern Recognition Receptors to Viral Replication Sites. PLoS Pathog 12:e1005428|
|Hong, MeeAe; Schwerk, Johannes; Lim, Chrissie et al. (2016) Interferon lambda 4 expression is suppressed by the host during viral infection. J Exp Med 213:2539-2552|
|Giugliano, Silvia; Petroff, Margaret G; Warren, Bryce D et al. (2015) Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission. J Immunol 195:3737-47|
|Kell, Alison; Stoddard, Mark; Li, Hui et al. (2015) Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length. J Virol 89:11056-68|