Hepatitis B virus (HBV) causes acute and chronic necroinflammatory liver disease and hepatocellular carcinoma (HCC). Over 350 million people worldwide are persistently infected by HBV, representing an enormous reservoir for horizontal and vertical spread of this virus to others. The long term objective of this application is to elucidate the pathogenesis of HBV infection with the ultimate hope that this knowledge will lead to the development of new therapeutic strategies to terminate persistent infection and its attendant costs and complications. HBV replicates noncytopathically in the hepatocyte, and most of the liver injury associated with this infection reflects the immune response. In contrast to many other viral infections, the innate immune response does not contribute significantly to the pathogenesis of liver disease or viral clearance, while the adaptive immune response contributes to both. Specifically, cytotoxic T lymphocytes (CTLs) play a major part in the development of liver disease and the resolution of HBV infection. Viral persistence reflects the failure to induce a sufficient CTL response, such that the infection is not cleared and a chronic necroinflammatory process begins, the end result of which is HCC. Using transgenic mice that replicate HBV at high levels in the liver as recipients of HBV-specific CTLs, along with normal inbred mice infected with hepatotropic, replication-deficient adenoviruses, we have recently shown that platelets play a crucial and previously unrecognized role in viral pathogenesis. Indeed, upon activation, platelets contribute to liver disease and viral clearance by promoting the recruitment of virus-specific CTLs into the liver. As indicated by preliminary results, this remarkable effect is most likely dependent on specific interactions between platelets and CTLs. Thus, it is conceivable that platelet/CTL interactions occurring within the hepatic microcirculation may direct CTLs to extravasate, reach parenchymal cells (i.e. hepatocytes) and perform pathogenetic and/or antiviral effector functions. The intrahepatic visualization and mechanistic understanding of platelet/CTL interactions represent major goals of this application. Additionally, we will perform experiments aimed at defining the impact that pharmacologic inhibition of platelet activation or activation-dependent events (including those affecting platelet/CTL interactions) may have on the severity of CTL-mediated liver injury. These studies will shed new light on previously unknown and important aspects of HBV pathogenesis, and they may provide new information for future treatments of chronic HBV infection in man. We are also confident that results from this grant application will have far-reaching pathogenetic implications, not only in related viral infections (i.e. hepatitis C virus), but also in other T cell-mediated pathological conditions such as autoimmunity, graft rejection or cancer. Public Health Relevance: Hepatitis B virus (HBV) cause acute and chronic liver diseases. Chronic HBV infection is associated with varying degrees of liver damage, and it often progresses to the development of life-threatening complications such as cirrhosis and cancer. Over 350 million people worldwide are chronically infected by this virus, and about 1 million of them die each year. The long term objective of this application is to use animal models to elucidate the pathogenesis of HBV infection with the ultimate hope that this knowledge will lead to the development of new therapeutic strategies to terminate persistent infection and its attendant costs and complications

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040696-15
Application #
8210916
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
1997-01-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2012
Total Cost
$464,322
Indirect Cost
$219,297
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Castagnaro, Laura; Lenti, Elisa; Maruzzelli, Sara et al. (2013) Nkx2-5(+)islet1(+) mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity. Immunity 38:782-91
Sitia, Giovanni; Iannacone, Matteo; Guidotti, Luca G (2013) Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. J Hepatol 59:1135-8
Guidotti, Luca G; Iannacone, Matteo (2013) Effector CD8 T cell trafficking within the liver. Mol Immunol 55:94-9
Tonti, Elena; Jimenez de Oya, Nereida; Galliverti, Gabriele et al. (2013) Bisphosphonates target B cells to enhance humoral immune responses. Cell Rep 5:323-30
Sitia, Giovanni; Iannacone, Matteo; Aiolfi, Roberto et al. (2011) Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog 7:e1002061
Iannacone, Matteo; Sitia, Giovanni; Guidotti, Luca G (2009) On the role of platelets in the pathogenesis of viral hepatitis. J Hepatol 51:599-600
Iannacone, Matteo; Sitia, Giovanni; Isogawa, Masanori et al. (2008) Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci U S A 105:629-34
Iannacone, Matteo; Sitia, Giovanni; Ruggeri, Zaverio M et al. (2007) HBV pathogenesis in animal models: recent advances on the role of platelets. J Hepatol 46:719-26
Iannacone, Matteo; Sitia, Giovanni; Narvaiza, Inigo et al. (2007) Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus. Clin Vaccine Immunol 14:1532-5
Sitia, Giovanni; Iannacone, Matteo; Muller, Susanne et al. (2007) Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice. J Leukoc Biol 81:100-7

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