Luca Guidotti


ERC advanced grant
Luca Guidotti, Head of Unit

Since more than 20 years, our laboratory has been working on the mechanistic elucidation of immunopathological processes that occur in the liver during acute or chronic infection with hepatitis B virus (HBV). HBV is the prototype member of the Hepadnaviridae family and it is a small DNA virus whose host range is restricted to humans and chimpanzees and whose tropism is restricted to the parenchymal cell of the liver, i.e. the hepatocyte. HBV persistently infects about 300 million people worldwide, and about 1 million of them die each year from the complications of chronic infection (e.g. cirrhosis and hepatocellular carcinoma, HCC). Owing to the use of animal models (mainly HBV transgenic mice and HBV-infected chimpanzees), we have shown that HBV replicates noncytopathically in the hepatocyte and that most of the clinical syndromes associated with this infection reflect the adaptive immune response, especially the virus-specific effector CD8+ T cell (CD8TE) response. We also showed that CD8TE effector functions promote the resolution of HBV infection and that viral persistence results from the failure to induce or maintain these CD8TE-dependent events. Although CD8TE are central to HBV pathogenesis, several other liver resident (including Kupffer cells and stellate cells) and non-resident (including platelets and polymorhonuclear or mononuclear antigen-nonspecific inflammatory cells) cells play distinctive roles in it, indicating that the host response to HBV is a highly complex but coordinated process. In spite of these accomplishments, however, a number of issues related to HBV pathogenesis remain unanswered, and they include the means by which CD8TE traffic and recognize antigen within the liver and how such processes are affected by the anatomical and hemodynamical changes that characterize acute versus chronic HBV infection. To tackle these and other unresolved issues, we are coupling dedicated mouse models of HBV infection with state-of-the-art static and dynamic imaging such as 3D confocal/light sheet fluorescence microscopy, correlative light and electron microscopy, multi-photon intravital microscopy, 7Tesla MRI and optical-computed tomography (see Research Activities).