Coronaviruses infect many species of animals including humans, causing diseases that range from mild to severe and from acute to chronic. The recently emerged SARS coronavirus is the first example of a severe disease in humans caused by a coronavirus. Murine coronavirus, mouse hepatitis virus (MHV), infection of the mouse provides a model for the study of encephalitis and chronic demyelinating diseases such as Multiple Sclerosis. Different strains of MHV display different tropisms and vastly different levels of neurovirulence. The outcome of MHV infection is determined by a combination of viral genes and host cell response. The highly neurovirulent RJHM strain of MHV spreads rapidly thoughout the central nervous system (CNS) inducing a minimal T cell response, resulting in a lack of viral clearance and mortality of all infected mice, even at very low doses. The more neuroattenuated RA59 strain spreads less extensively in the CNS and induces a robust T cell response, resulting in viral clearance;surviving mice develop a chronic demyelinating disease. A chimeric recombinant virus (SJHM/RA59), expressing the JHM spike gene within the background of A59, like RJHM, spreads rapidly in the CNS but, like RA59, induces a robust CD8T cell response. Thus both spike and background genes contribute to the high neurovirulence of RJHM. RJHM is thought to infect and spread more extensively in neurons than RA59;however, such tropism has not been confirmed. Recent evidence suggests that RJHM, unlike RA59, can induce lethal CNS disease in the absence of the only known MHV receptor, CEACAM1a;this mechanism likely contributes to the extensive viral spread observed during RJHM infection. Thus, we hypothesize that the following two mechanisms could contribute to the enhanced neurovirulence of RJHM: RJHM infects and spreads more efficiently in the CNS, at least in part due to its capacity for CEACAM1a-independent spread and RJHM elicits a weak antiviral T cell response which results from an inability to prime a CD8T cell response in the CNS. We will test this hypothesis by 1) comparison of the neural cellular tropism and the cytokines induced by RJHM and RA59 infection of neural cell types, using primary cultures of neurons and glial cells;2) investigation of the role of the CEACAM1a receptor in spread of RJHM and RA59 in vitro in neural cell cultures and in vivo and 3) comparison of CNS infection with RJHM as compared with RA59 as far as spread of viral antigen into the cervical lymph nodes (CLN) and its impact on antigen presentation. These studies will add to the understanding of how closely related viruses may have very different tropisms and levels of neurovirulence, and induce different immune responses. Such studies will be applicable to understanding the pathogenesis of virus-induced CNS disease and, in the long term, contribute to vaccine design.

Public Health Relevance

Infection of mice with the coronavirus, mouse hepatitis virus (MHV), provides a model system for the study of encephalitis and demyelination and is used as an animal model for Multiple Sclerosis. This proposal is aimed at understanding how 1) the types of neural cells infected, 2) the interaction of MHV with the viral receptor CEACAM1a and 3) the type and extent of immune response induced, contribute to the level of virulence following MHV infection of the central nervous system (CNS). Such studies will be applicable to understanding the pathogenesis of virus-induced CNS disease and, in the long term, contribute to vaccine design. .

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060021-23
Application #
8389557
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
1985-07-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
23
Fiscal Year
2013
Total Cost
$284,656
Indirect Cost
$100,397
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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