Role of Kupffer Cell and NK Cell Interactions in Hepatitis C Virus Infektion

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The pathogenesis of Hepatitis C Virus (HCV)-induced liver cirrhosis is thought to be driven by the host immune system itself. KCs represent the resident macrophage population in the liver and it has been shown that they are activated and increased in frequency in the liver of chronic HCV-infected patients. Furthermore, in response to HCV, Kupffer cells (KCs) release IL-1b and IL-18 in vitro. However, a direct effect of HCV-exposed KCs on HCV replication is still unknown and the interaction between KCs and liver-infiltrating Natural Killer (NK) cells in response to HCV-replication is not studied in detail yet. This is surprising, since NK cells represent a major effector cell population involved in innate immune responses to viral infections and a Toll-like receptor (TLR)-dependent crosstalk with KCs has been described. In patients with chronic HCV infection the frequency of intrahepatic NK cells is higher and they are more activated compared to those in the peripheral blood. They display a functional dichotomy characterized by reduced production of IFNg and enhanced cytotoxicity, probably contributing to the liver injury as NK cell cytotoxicity correlates to ALT levels. Furthermore, we were recently able to link inflammasome-mediated IL-18 secretion by peripheral blood monocytes with NK cell derived IFNg production. A limitation of many previous studies is the use of mononuclear cell populations only from the blood. Indeed, it has been shown that composition and function of mononuclear cells differs between blood and liver. Therefore, the true interaction between liver mononuclear cells can only be determined through testing of cells derived from liver tissue. Taking advantage of hepatobiliary transplant surgery being performed in our department, this project is proposing to study innate immune cells in the context of HCV replication specifically in the liver, the biological more relevant compartment. In a first step, we are going to analyze the interplay of liver resident KCs and intrahepatic NK cells in response to HCV by using the HCV replicon system. We will address the question if KCs exert a direct antiviral effect and whether they also have an indirect antiviral effect via NK cell-derived IFNg production. In a second part, we will confirm our observation by using liver tissue from chronic HCV-infected patients. We will establish whether KCs from patients with chronic HCV infection have reduced TNFa-mediated (direct) and NK-cell mediated (indirect) antiviral effects and if the functional impairment of intrahepatic NK cells is reversible by using KCs from healthy controls. Finally, by following HCV+ patients prospectively during a course of HCV treatment with IFN-free direct-acting antivirals (DAAs), we will study the effect of a complete removal of the virus on peripheral innate immune cells comparing pre and post OLT patients.