Hepatitis C virus (HCV) is an emerging infectious disease. Patients exposed to this virus frequently fail to clear this viral infection and become chronic carriers. Chronic infection by this virus can lead to severe liver diseases including cirrhosis and hepatocellular carinoma. How HCV evades host immunity to establish chronic infection, however, remains largely unclear. Studies in recent years indicate that HCV can suppress intracellular antiviral responses. The goal of this research project is to further investigate how HCV interacts with its host cells to evade intracellular innate immunity. RIG-I is an important pattern recognition receptor (PRR) in cells and its activation can lead to a cascade of antiviral responses. Recent studies indicate that HCV can disrupt RIG-I signaling. Thus, the goal of specific aim 1 of this project is to further investigate the interactions between HCV and RIG-I signaling. PKR is a double-stranded RNA dependent protein kinase. It is another important PRR in cells. Its activation will result in the inactivation of the translation initiation factor elF2alpha for the suppression of cellular and viral protein synsthesis. Our recent studies indicate that HCV could induce the phophorylation of elF2alpha, which does not appear to suppress HCV replication. Thus, the goal of specific aim 2 is to further investigate the role of PKR and elF2alpha in anti-HCV response. Autophagy is an important arm of innate immunity. It can remove intracellular pathogens including viruses and is also critical for delivering cytosolic viral RNA to endosomes for the activation of toll-like receptor 7 (TLR7). Our recent studies indicated that HCV could suppress the fusion between autophagosomes and endosomes/lysosomes. This effect of HCV on host cells may be important for preventing the activation of TLR7. The goal of specific aim 3 is to further investigate how HCV perturbs the autophagic pathway and to study the possible effect of this perturbation on the activation of TLR7. The research of this project will lead to a better understanding of the interaction between HCV and its host cells. Thus, it will contribute positively to this Program to enhance the understanding of how host cells control viral replication and how viruses suppress intracellular antiviral defenses.

Public Health Relevance

HCV is an important human pathogen. Our proposed research will lead to a better understanding of the life cycle of HCV. This understanding will be important for the improvement of treatments for HCV patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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University of Southern California
Los Angeles
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Sánchez-Aparicio, Maria T; Feinman, Leighland J; García-Sastre, Adolfo et al. (2018) Paramyxovirus V Proteins Interact with the RIG-I/TRIM25 Regulatory Complex and Inhibit RIG-I Signaling. J Virol 92:
Do?anay, Sultan; Lee, Maurice Youzong; Baum, Alina et al. (2017) Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression. Integr Biol (Camb) 9:857-867
Sánchez-Aparicio, Maria Teresa; Garcin, Dominique; Rice, Charles M et al. (2017) Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA. J Gen Virol 98:1282-1293
Chen, Chia-Lin; Huang, Jeffrey Y; Wang, Chun-Hsiang et al. (2017) Hepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2. Nat Commun 8:13882
Nelson, Emily V; Schmidt, Kristina M; Deflubé, Laure R et al. (2016) Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions. J Virol 90:7268-7284
Pisanelli, Giuseppe; Laurent-Rolle, Maudry; Manicassamy, Balaji et al. (2016) La Piedad Michoacán Mexico Virus V protein antagonizes type I interferon response by binding STAT2 protein and preventing STATs nuclear translocation. Virus Res 213:11-22
Zhang, Jichuan; Fei, Jingyi; Leslie, Benjamin J et al. (2015) Tandem Spinach Array for mRNA Imaging in Living Bacterial Cells. Sci Rep 5:17295
Weber, Michaela; Sediri, Hanna; Felgenhauer, Ulrike et al. (2015) Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. Cell Host Microbe 17:309-319
Wang, Linya; Tian, Yongjun; Ou, Jing-hsiung James (2015) HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Pathog 11:e1004764
Lee, Jiyoung; Tian, Yongjun; Chan, Stephanie Tze et al. (2015) TNF-? Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism. PLoS Pathog 11:e1004937

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