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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
American Association for the Study of Liver Diseases/American Liver Foundation Liver Scholar Award
University of Colorado School of Medicine/Denver VA Medical Center
Project Title: Hepatitis C virus stimulation of immune regulatory galectin-9 production by Kupffer cells
Hepatitis C virus (HCV) chronically infects 1-2% of the US population leading to cirrhosis in 20% of those infected over 20 years. The mechanism of chronicity is poorly understood. Dr. Mengshol, along with his mentors Dr. Golden-Mason and Dr. Rosen, recently demonstrated that the immune regulatory protein galectin-9 (gal-9) is dramatically increased in the liver and plasma of HCV patients. Dr Rosen’s group showed that gal-9 triggers apoptosis of HCV specific T cells and increases regulatory T cells. Blockade of this pathway restores CD8 T cell function. Dr. Mengshol hypothesizes that HCV stimulation of the immune inhibitor gal-9 contributes to persistent infection.
Liver Kupffer cells (macrophages) produce gal-9 during HCV infection. Dr. Mengshol now shows that HCV infected cells trigger gal-9 mRNA production in a monocyte/macrophage cell line. Using quantitative PCR and western blotting, he proposes to study the mechanisms regulating gal-9 expression by examining the response of normal human monocytes, macrophages, and Kupffer cells to HCV infected cells. He will also compare the response of cells from HCV-infected patients. In addition, he will examine the role that macrophage differentiation plays in regulation of the gene.
First, Dr. Mengshol will examine the molecular mechanism that HCV triggers in KC and macrophages to stimulate gal-9 production. Because HCV is an RNA virus, he hypothesizes that Macrophage/KC uptake of HCV infected cells into endosomes will trigger signaling via endosomal toll-like receptor 3(TLR3) leading to stimulation of gal-9 gene transcription. Second, he will study whether contact and uptake of HCV infected cells is required for gal-9 expression. Next, he will verify that TLR3 and phagocytosed HCV infected cells co-localize. Finally, Dr. Mengshol will study whether TLR3 expression is required for gal-9 induction by using siRNA inhibition of TLR3 expression and he will study the downstream signaling pathways activated leading to gal-9 expression.
Understanding the mechanism triggering gal-9 expression should lead to a better understanding of the immune sequelae of chronic viral infection and may lead to novel immune-modulating therapies for HCV.