My research interests include the study of innate and adaptive immune responses to viral infections, in particular infections of the liver. Much of my work has focused on hepatitis B (HBV) and hepatitis C (HCV) infections, which affect about 500 million people worldwide. The spectrum of disease ranges from acute to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Although HBV infection can be prevented by a vaccine, there is still no curative treatment for most who are already chronically infected because antiviral agents do not eliminate the transcriptional template of HBV, the covalently closed circular DNA. For HCV, a vaccine has not yet been developed.
A major emphasis of my research program has been the identification of innate and adaptive immune responses that mediate viral clearance and the analysis of mechanisms of viral immune evasion. My laboratory is also studying immunological mechanisms responsible for the progression of chronic liver disease and mechanisms mediating liver-specific tolerance. We employ multidisciplinary approaches that include the study of biological samples from patients who are being followed by the NIDDK Liver Diseases Branch, as well as mouse models of liver infection (LCMV) and virological in vitro models.
In both HBV and HCV infections, chronic liver disease is thought to be immune-mediated. The rate of liver disease progression to liver cirrhosis varies greatly among infected individuals, and the factors that regulate inflammation and disease progression are largely unknown. In particular, my laboratory is interested in analyzing the role of innate immune responses—in particular those mediated by innate cytokines and natural killer cells—in chronic liver inflammation.
The liver is known to have tolerogenic capacities that downregulate immune responses to gut-derived antigens and, upon organ transplantation, to organs that are cotransplanted with the liver. Following up on observations that the laboratory made in patients, we are now studying tolerance mechanisms in the liver.