Hepatitis C virus (HCV) exacts a heavy toll on global health by causing acute and chronic hepatitis, cirrhosis, as well as hepatocellular carcinoma. Paradoxical to this cold reality, there is no vaccine available to prevent the infection, and combination therapy with pegylated IFN-a and ribavirin is only effective in 40-80% of patients and has severe side effects. Fortunately, with the recently developed infectious clones, we are finally able to dissect the entire viral life cycle at the molecular level. It is conceivable that novel antiviral therapies and treatment regimens relieving HCV associated pathologies will become available within foreseeable future given the accelerated pace of research. As far as what this application concerns, accumulating evidence has highlighted the importance of tight junction (TJ) in HCV entry. Specifically, we and others reported that the tight junction protein occludin (OCLN) is indispensible for HCV envelope protein-dependent entry. Evidence also indicated that OCLN partially accounts for the narrow host range of HCV. However, murine cells expressing all known human (co-)receptors remained resistant to cell culture grown HCV (HCVcc) infection, suggesting either additional human factors are required or dominant inhibitors exist in murine cells. Interestingly, we observed that both OCLN and claudin-1 were downregulated in HCVcc-infected hepatoma cells. Subsequent study suggested that OCLN is increasingly cleaved in HCV infected cells. In light of these findings, we believe novel therapeutics, novel infection systems, and novel insights in understanding HCV-associated pathogenesis may be developed. We hypothesize that antibody against OCLN extracellular loops or OCLN-derived peptide may block the spreading of virus (to be tested in Aim 1);additional host factors are required to support optimal HCV infection in murine cells or restriction factors exist in these cells (to be tested in Aim 2);downregulation of TJ proteins during HCV entry may alter cell physiology (to be tested in Aim 3). We plan to test the hypotheses by (i) assessing the effect of antibodies against OCLN or OCLN-derived peptides on HCV entry. (ii) identifying host factors promoting or restricting HCV infection of murine cells. (iii) analyzing the impact of HCV infection on TJ integrity and hepatocyte functions.
HCV infection poses a serious threat to US public health and there is currently no vaccine available. Completion of the proposed research will shed lights to the development of novel therapeutics, small animal models, and to our understanding of HCV-associated pathogenesis.
|Peng, Hui; Ning, Huan; Wang, Qinghong et al. (2018) Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing TH2 cells through the Notch/Gata3 pathway. J Allergy Clin Immunol 142:582-594.e10|
|Lin, Shih-Chao; Kappes, Matthew A; Chen, Mei-Chun et al. (2017) Distinct susceptibility and applicability of MDCK derivatives for influenza virus research. PLoS One 12:e0172299|
|Liu, Shufeng; Zhao, Ting; Song, BenBen et al. (2016) Comparative Proteomics Reveals Important Viral-Host Interactions in HCV-Infected Human Liver Cells. PLoS One 11:e0147991|
|Liu, Shufeng; DeLalio, Leon J; Isakson, Brant E et al. (2016) AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus. Circ Res 119:1183-1189|
|Li, Hongmei; Wang, Tony T (2016) MCPIP1/regnase-I inhibits simian immunodeficiency virus and is not counteracted by Vpx. J Gen Virol 97:1693-8|
|Wei, Dahai; Li, Nan L; Zeng, Yanli et al. (2016) The Molecular Chaperone GRP78 Contributes to Toll-like Receptor 3-mediated Innate Immune Response to Hepatitis C Virus in Hepatocytes. J Biol Chem 291:12294-309|
|Li, Hongmei; He, Hui; Gong, Leyi et al. (2016) Short Communication: Preferential Killing of HIV Latently Infected CD4(+) T Cells by MALT1 Inhibitor. AIDS Res Hum Retroviruses 32:174-7|
|Huang, Shengping; Liu, Shufeng; Fu, Jia J et al. (2015) Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation. J Biol Chem 290:20782-92|
|Liu, Shufeng; Wang, Wenyu; Brown, Lauren E et al. (2015) A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway. EBioMedicine 2:1600-6|
|Liu, Baoming; Li, Nan L; Wang, Jie et al. (2014) Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus. J Virol 88:13821-35|
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