HCV Infection and Innate Immunity of the Liver

Mark S. Orloff, MD, Director Living Donor Liver Transplant Program

Research Overview

HCV Infection and Innate Immunity of the Liver

Innate immunity forms the first line of host defense toward infection. Pathogens that establish chronic infection, such as Hepatitis C virus, are adept at subverting innate immunity in order to establish a niche for infection. At the center of these interactions is the integrated macrophage – NK cell response, and with respect to immune responses in the liver, by the interaction between Kupffer cells and NK cells. We have developed an experimental model to analyze Kupffer cell - NK cell crosstalk using primary human cells activated via Toll-like receptors. This model is subverted by HCV encoded factors. Currently, we are exploring: 1) subversion of crosstalk by HCV proteins, 2) the TLR-ligand induced signal transduction of human lymphocytes; 3) The regulation of IFN-gamma message stability in NK cells and 4) inherent biologic variation in an individual’s response and its consequences for the reinfection of liver transplants by HCV. These studies will add significant insight into the mechanisms of innate response to HCV for the purpose of developing therapeutic strategies and assessing magnitude of an individual’s response for clinical decision making. This model of innate immunity in the context of liver transplantation is unique in its utility for exploring de novo infection of a pristine liver since the initiating point of chronic viral infections is nearly impossible to define in human populations by other approaches.

Senior Postdoctoral Research Associates

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