Hepatitis C and hepatitis B virus infections in humans are characterized by hepatocellular necrosis, inflammation, and development of hepatoma. There is evidence suggesting that virus-induced hepatitis is related to an inefficient innate immune response;however, the exact cellular and molecular mechanisms leading to disease remain elusive. We propose to use a murine coronavirus, mouse hepatitis virus (MHV), that induces hepatitis in a strain specific manner, to evaluate both viral genetic determinants and host intrahepatic innate immune responses underlying pathogenesis. We have previously established that the spike glycoprotein and other genes in the 3'one third of the MHV genome determine the ability to replicate in the liver and the corresponding severity of liver damage. Both hepatotropic and non-hepatotropic strains of MHV replicate in primary hepatocytes;however, non-hepatotropic strains fail to replicate in the liver in vivo. We will use chimeric recombinant viruses, that induce different levels of hepatitis to test the hypothesis that liver sinusoidal endothelial cells (LSEC) and/or Kupffer cells restrict entry and/or replication in the liver of non-hepatotropic strains. Infection of mice with these MHV strains will also be used to uncover mechanisms by which MHV manipulates the host innate immune responses to favor viral replication. Characterization of the recruitment and activity of immune cells and the cytokine/chemokine environment in the infected liver will be carried out to identify factors contributing to the pathogenesis of hepatitis. Elucidation of the mechanism of MHV induced demyelination will contribute to the understanding of hepatitis in humans and in the long term contribute to the design of anti-viral therapies.

Public Health Relevance

Hepatitis is a pathological syndrome of liver injury that has several causes and is characterized by varying degrees of liver injury. Chronic hepatitis C and hepatitis B virus infections in humans result in liver damage, inflammation, and secondary development of liver cancer. The necessity for liver transplants as a result of HCV and HBV infection has become a serious public health issue;however, broadly effective therapies to eliminate infection are not currently available. It is believed that virus-induced hepatitis is in part due to an inefficient immune response, but the exact mechanisms leading to disease remain elusive. We propose to use a murine coronavirus, mouse hepatitis virus (MHV), which induces hepatitis in mice, to evaluate both viral and host factors underlying pathogenesis. We will use MHV strains, that induce different levels of hepatitis to test the hypothesis that liver sinusoidal endothelial cells and/or Kupffer cells restrict entry and/or replication in the liver of non- hepatotropic strains. Infection of mice with these MHV strains will also be used to uncover mechanisms by which MHV manipulates the host immune responses to favor viral replication. Characterization of the recruitment and activity of immune cells and the cytokine/chemokine environment in the infected liver will reveal factors contributing to the pathogenesis of hepatitis. Elucidation of the mechanism of MHV induced demyelination will contribute to the understanding of hepatitis in humans and in the long term contribute to the design of anti-viral therapies

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI080797-02
Application #
7847581
Study Section
Special Emphasis Panel (ZRG1-IDM-P (91))
Program Officer
Park, Eun-Chung
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$236,250
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Zhao, Ling; Rose, Kristine M; Elliott, Ruth et al. (2011) Cell-type-specific type I interferon antagonism influences organ tropism of murine coronavirus. J Virol 85:10058-68
Leibowitz, Julian L; Srinivasa, Rajiv; Williamson, Shawn T et al. (2010) Genetic determinants of mouse hepatitis virus strain 1 pneumovirulence. J Virol 84:9278-91