Viral infections of the central nervous system (CNS) can cause both acute and chronic diseases that devastate the host. This proposal aims to investigate the extent and effectiveness of the host's type I interferon (IFN) response in restricting virus replication and spread in the CNS, and in addition, the mechanisms used by viruses to antagonize the IFN response. Infection of mice with the murine coronavirus, mouse hepatitis virus (MHV), offers a convenient and compelling model for studying virus-induced encephalitis and chronic demyelinating diseases such as multiple sclerosis (MS). Using a collection of viral strains and mutants that display different tropisms and virulence levels, we showed previously that the extent of MHV neurovirulence depends on a combination of viral and host factors, including the type I IFN response (primarily IFN-?/?), an early and crucial response to viral invasion. MHV infects several CNS cell types, including neurons and glial cells, cells types that have been reported to express interferon-stimulated genes (ISGs) during infection of the CNS with multiple viruses. However, the basal expression level of these ISGs, crucial for detection of viral invasion and antiviral response, is lower in the brain compared with other organs. Consequently, the CNS may be less prepared to quickly respond to viral invasion. Also contributing to the virus-host interactions, MHV encodes multiple type I IFN antagonists, most notably the ns2 protein that confers antagonism of the potent antiviral 2',5'-oligoadenylate synthetase-ribonuclease L (OAS-RNaseL) pathway that is induced by IFN. In addition the highly neurovirulent JHM.WU strain antagonizes IFN- ?/? induction. Based on these findings, we propose to use the mildly neurovirulent A59 strain as well as JHM.WU to test the following overall hypothesis: IFN- ?/? signaling in the CNS can effectively restrict neurovirulent MHV spread in vivo. At the same time MHV has the ability to compromise the type I IFN response through cell-type specific IFN antagonism. The virus-host balance will depend on the tissue and cell types infected and virus strain-specific proteins that compromise the IFN-?/? response. The following aims are proposed: 1) Determine the cell types that restrict neurovirulent MHV infection in the CNS in vivo, using A59 and JHM.WU along with mice deficient in type I IFN receptor expression, specifically in macrophage/microglia, neuroectodermal cells or neurons;2) Investigate the effectiveness of the OAS-RNaseL pathway in limiting MHV induced pathology during acute and chronic CNS infection and 3) Map the genes and investigate the mechanisms underlying type I IFN antagonism and high neurovirulence of JHM.WU. Understanding the immune mechanisms and the CNS cell types that limit viral pathogenesis and characterizing the strategies used by neurovirulent MHV to evade the host type I IFN response will likely aid in the development of better therapeutics to treat virus-induced encephalitis in humans. Moreover, understanding type I IFN signaling in the CNS may aid in developing or refining therapeutic applications for type I IFNs, which are currently used in treatment of MS and hepatitis C.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS081008-03
Application #
8663329
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhao, Ling; Birdwell, L Dillon; Wu, Ashley et al. (2013) Cell-type-specific activation of the oligoadenylate synthetase-RNase L pathway by a murine coronavirus. J Virol 87:8408-18