C57BL/6 mice infected with the neurotropic rJ2.2 variant of the JHM strain of mouse hepatitis virus (rJ2.2) develop acute and chronic demyelinating encephalomyelitis and thereby serve as a useful model for the human disease multiple sclerosis. The overall objective of this project has been to understand virus-host interactions, to enhance virus clearance and minimize tissue damage. In the past funding period, we concentrated on aspects of the T cell response that were pathogenic but protective and others that were regulatory, dampening CD4 T cell-mediated immunopathological changes. However, before a T cell response can clear virus, the host must mount a well-orchestrated and robust innate immune response. Our recent work has focused on two aspects of this early innate response, both involving microglia, which are the resident myeloid cells in the CNS. First, we showed that microglia are critical for protection. Although microglia have important roles in immune surveillance and maintenance of homeostasis in the CNS, their role in the context of infection remains ill-defined. Our results show that they are key for protection from rJ2.2 infection. Second, we found that signaling of a single eicosanoid, prostaglandin D2 (PGD2), through its DP1 receptor, found on myeloid cells including microglia, was required for optimal survival in rJ2.2-infected mice. In the absence of DP1 signaling, type 1 IFN (IFN-I) expression was delayed and IL-1? expression was increased, suggesting that PGD2/DP1 signaling was critical for a balanced immune response. The absence of PGD2/DP1 signaling resulting in dysregulated microglia function. Therefore, the central objective of this project is to better understand the many roles that microglia have in enhancing the host response to viral infections in the brain and thereby improving outcomes in the context of viral encephalitis (and ultimately, demyelinating disease). This objection will be addressed in the following specific aims.
Specific Aim 1 : To determine the basis for lethal outcomes in microglia-depleted rJ2.2-infected mice. In this aim, mice will be treated with PLX6522, which depletes microglia. We will monitor virus clearance and immune function after treatment. We will assess whether macrophage numbers, function or gene expression is changed in the absence of microglia.
Specific Aim 2 : To determine the role of PGD2/DP1 signaling in microglia in rJ2.2-infected mice. In this aim, we will assess effects of PGD2/DP1 on viral control and the host immune response. We found that a PYRIN domain only protein, PYDC3, was downregulated in microglia of mice lacking DP1 signaling. PYDC3 has similarities to IFN-I-inducible human proteins that regulate inflammasome formation and activation but homologous proteins have not been identified in mice. One of the goals of this aim is to understand the interactions and roles of prostaglandin D2 signaling, IFN-I expression and inflammasome function.
Viral infections of the central nervous system cause short term neurological defects and often, even if subclinical, have long term sequelae. This application is directed at understanding protective aspects of the anti-virus immune response, with focus on microglia and on eicosanoids and their signaling pathways. Enhanced understanding of the role of these cells and molecules in viral pathogenesis may identify novel therapeutic targets.
|Perlman, Stanley; Gallagher, Tom (2018) Not your usual tRNA synthetase: hWARS serves as an enterovirus entry factor. J Clin Invest 128:4767-4769|
|Fehr, Anthony R; Jankevicius, Gytis; Ahel, Ivan et al. (2018) Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol 26:598-610|
|Wheeler, D Lori; Sariol, Alan; Meyerholz, David K et al. (2018) Microglia are required for protection against lethal coronavirus encephalitis in mice. J Clin Invest 128:931-943|
|Athmer, Jeremiah; Fehr, Anthony R; Grunewald, Matthew E et al. (2018) Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses. MBio 9:|
|Grunewald, Matthew E; Fehr, Anthony R; Athmer, Jeremiah et al. (2018) The coronavirus nucleocapsid protein is ADP-ribosylated. Virology 517:62-68|
|Hua, Xiaoyang; Vijay, Rahul; Channappanavar, Rudragouda et al. (2018) Nasal priming by a murine coronavirus provides protective immunity against lethal heterologous virus pneumonia. JCI Insight 3:|
|Vijay, Rahul; Fehr, Anthony R; Janowski, Ann M et al. (2017) Virus-induced inflammasome activation is suppressed by prostaglandin D2/DP1 signaling. Proc Natl Acad Sci U S A 114:E5444-E5453|
|Perlman, Stanley; Zhao, Jingxian (2017) Roles of regulatory T cells and IL-10 in virus-induced demyelination. J Neuroimmunol 308:6-11|
|Wheeler, D Lori; Athmer, Jeremiah; Meyerholz, David K et al. (2017) Murine Olfactory Bulb Interneurons Survive Infection with a Neurotropic Coronavirus. J Virol :|
|Athmer, Jeremiah; Fehr, Anthony R; Grunewald, Matthew et al. (2017) In Situ Tagged nsp15 Reveals Interactions with Coronavirus Replication/Transcription Complex-Associated Proteins. MBio 8:|
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