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The CSF1R-Microglia Axis Has Protective Host-Specific Roles During Neurotropic Picornavirus Infection
John Michael S Sanchez1, Ana Beatriz DePaula-Silva1, Daniel J Doty1
1Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States.
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.
Insights
Microglia depletion via CSF1R inhibition causes fatal encephalitis in one mouse strain but worsens demyelination in another, revealing strain-specific roles in viral brain infections.
Area of Science:
- Neuroimmunology
- Virology
- Cellular Biology
Background:
- Viral encephalitis presents varied outcomes, with microglia's role in antiviral responses unclear.
- Microglia, CNS-resident antigen-presenting cells, are crucial for detecting viral infections.
Purpose of the Study:
- Investigate the CSF1R-microglia axis's role in neurotropic picornavirus infection.
- Determine strain-specific differences in microglial responses to viral insults.
Main Methods:
- Used Theiler's murine encephalomyelitis virus (TMEV) and CSF1R inhibitor PLX5622 in C57BL/6J and SJL/J mice.
- Analyzed viral clearance, neurological disease, and immune cell profiles (microglia, T cells).
Main Results:
- CSF1R inhibition caused fatal encephalitis in C57BL/6J mice, reducing microglial MHC-II and increasing T cell inflammation.
- In SJL/J mice, CSF1R inhibition exacerbated demyelination, with altered T cell responses and broad immunosuppression upon chronic inhibition.
- Demonstrated strain-specific microglial antigen presentation and T cell crosstalk impacting viral susceptibility.
Conclusions:
- The CSF1R-microglia axis plays a critical, strain-dependent role in neurotropic viral encephalitis.
- Microglial function and T cell interactions significantly influence disease outcomes in viral CNS infections.
