Abstract
Viral encephalitis is a major cause of morbidity and mortality, but the manifestation of disease varies greatly between individuals even in response to the same virus. Microglia are professional antigen presenting cells that reside in the central nervous system (CNS) parenchyma that are poised to respond to viral insults. However, the role of microglia in initiating and coordinating the antiviral response is not completely understood. Utilizing Theiler’s murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, and PLX5622, a small molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R) signaling that can deplete microglia in the CNS; we investigated the role of the CSF1R-microglia axis in neurotropic picornavirus infection of C57BL/6J and SJL/J mice. These mouse strains differ in their ability to clear TMEV and exhibit different neurological disease in response to TMEV infection. CSF1R antagonism in C57BL/6J mice, which normally clear TMEV in the CNS, led to acute fatal encephalitis. In contrast, CSF1R antagonism in SJL/J mice, which normally develop a chronic CNS TMEV infection, did not result in acute encephalitis, but exacerbated TMEV-induced demyelination. Immunologically, inhibition of CSF1R in C57BL/6J mice reduced major histocompatibility complex II expression in microglia, decreased the proportion of regulatory T cells in the CNS, and upregulated proinflammatory pathways in CNS T cells. Acute CSF1R inhibition in SJL/J mice had no effect on microglial MHC-II expression and upregulated anti-inflammatory pathways in CNS T cells, however chronic CSF1R inhibition resulted in broad immunosuppression. Our results demonstrate strain-specific effects of the CSF1R-microglia axis in the context of neurotropic viral infection as well as inherent differences in microglial antigen presentation and subsequent T cell crosstalk that contribute to susceptibility to neurotropic picornavirus infection.
Highlights
In the United States, an estimated 6000 people per year are hospitalized for viral encephalitis at a total cost of up to $540 million annually [1]
We have previously shown that depletion of microglia in B6J mice using PLX5622 results in fatal viral encephalitis when challenged with i.c
Theiler’s murine encephalomyelitis virus (TMEV) infection, even with as little as 40 plaque forming units (PFUs) of TMEV [11]. Based on this previous observation, we first sought to investigate whether colony-stimulating factor 1 receptor (CSF1R)-mediated depletion of microglia in B6J and SJL mice would affect the acute infiltration of peripheral immune cells into the central nervous system (CNS) in response to TMEV infection
Summary
In the United States, an estimated 6000 people per year are hospitalized for viral encephalitis at a total cost of up to $540 million annually [1]. Vaccination strategies and antiviral agents, including acyclovir and foscarnet, have been efficacious against select neurotropic viruses. Immunomodulatory agents are used in the context of acute viral encephalitis, either when no vaccine or antimicrobial drug is available or as an adjunct therapy, with limited benefit [1, 2]. Microglia are myeloid cells that are uniquely found in the central nervous system (CNS) parenchyma and are ideally situated to respond to neurotropic viruses, but the role of microglia in viral encephalitis is not completely understood. Among the first immune cells to respond to viral insult in the CNS, microglia may be critical determinants for the subsequent steps of the antiviral response
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