Hepatitis C virus (HCV) infection remains a major global health problem. An estimated 180 million people worldwide and 4 million people in the United States are infected with HCV. Chronic HCV infection remains a major cause of cirrhosis and hepatocellular carcinoma (HCC). Despite recent advances in direct acting antivirals (DAA), some patients experience end stage liver disease progression. Thus, it is essential to understand the underlying mechanisms of HCV mediated liver disease progression for new therapeutic targets. In our current grant period, we made several important observations. We demonstrated that HCV infection induces autophagy for protection of virus growth, and impairs interferon (IFN) signaling mechanisms at multiple steps. We have also shown that HCV induces IL-1? secretion from macrophages without clearing virus from hepatocytes. Further, we identified a group of microRNAs (miRNAs) that are elevated in sera of chronically HCV-infected liver fibrosis patients. Emerging evidence suggests that exosomes are newly identified vehicle carrying circulating miRNAs for intercellular communications and little is known about their role in HCV mediated liver disease. We further observed a group of miRNAs is modulated during HCV infection within hepatocytes. Based on our preliminary results, we hypothesize that HCV induced miRNAs in hepatocytes are transported by exosomes to hepatic stellate cells (HSCs)/Kupffer cells (KCs), and play critical roles in HCV-mediated liver pathogenesis. We also predict that modulation of intracellular miRNAs following HCV infection alters hepatocyte growth. To test our hypothesis, we propose the following specific aims: (1) determine the role of HCV induced miRNAs transported through exosomes (exo-miR) in causing hepatic stellate cell activation, (2) determine the mechanism by which HCV stimulates inflammatory cytokines in macrophages/Kupffer cells and exert functional consequence on other liver cell types, and (3) investigate the role of HCV induced intracellular miRNA in primary human hepatocyte growth promotion. Understanding the cross-talk among liver cells will provide in-depth mechanism of HCV mediated liver disease progression and will help in identifying additional therapeutic targets.

Public Health Relevance

HCV infection is a major cause of progressive liver disease. The mechanisms by which HCV promotes fibrosis, cirrhosis and/or hepatocellular carcinoma are poorly understood. We will undertake an in-depth mechanistic study to understand HCV-mediated liver disease progression for development of effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK081817-06A1
Application #
9039872
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Doo, Edward
Project Start
2008-07-01
Project End
2021-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Pathology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Ray, Ratna B; Ray, Ranjit (2018) Hepatitis C virus manipulates humans as its favorite host for long term relationship. Hepatology :
Sur, Subhayan; Sasaki, Reina; Devhare, Pradip et al. (2018) Association between MicroRNA-373 and Long Noncoding RNA NORAD in Hepatitis C Virus-Infected Hepatocytes Impairs Wee1 Expression for Growth Promotion. J Virol 92:
Devhare, Pradip B; Ray, Ratna B (2018) Extracellular vesicles: Novel mediator for cell to cell communications in liver pathogenesis. Mol Aspects Med 60:115-122
Devhare, Pradip B; Sasaki, Reina; Shrivastava, Shubham et al. (2017) Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells. J Virol 91:
Sasaki, Reina; Devhare, Pradip B; Steele, Robert et al. (2017) Hepatitis C virus-induced CCL5 secretion from macrophages activates hepatic stellate cells. Hepatology 66:746-757
Meyer, Keith; Kwon, Young-Chan; Ray, Ratna B et al. (2017) N-terminal gelsolin fragment potentiates TRAIL mediated death in resistant hepatoma cells. Sci Rep 7:12803
Sasaki, Reina; Devhare, Pradip; Ray, Ratna B et al. (2017) Hepatitis C virus-induced tumor-initiating cancer stem-like cells activate stromal fibroblasts in a xenograft tumor model. Hepatology 66:1766-1778
Shrivastava, Shubham; Devhare, Pradip; Sujijantarat, Nanthiya et al. (2016) Knockdown of Autophagy Inhibits Infectious Hepatitis C Virus Release by the Exosomal Pathway. J Virol 90:1387-96
Bhattacharya, Sourav; Steele, Robert; Shrivastava, Shubham et al. (2016) Serum miR-30e and miR-223 as Novel Noninvasive Biomarkers for Hepatocellular Carcinoma. Am J Pathol 186:242-7
Meyer, Keith; Kwon, Young-Chan; Liu, Shuanghu et al. (2015) Interferon-? inducible protein 6 impairs EGFR activation by CD81 and inhibits hepatitis C virus infection. Sci Rep 5:9012

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