Abstract Details

Title Protective Host-Specific Roles of Microglia and CSF1R Signaling During Neurotropic Picornavirus Infection

Topic Infectious Disease

Presentation(s) Infectious Disease Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 037

Objective Microglia are the only resident myeloid cells in the central nervous system (CNS) parenchyma and are poised to respond to viral insults. Inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling can be used to deplete microglia in the CNS. This work aims to define the role of microglia and CSF1R signaling in acute and chronic neurotropic picornavirus infection.

Background Viral encephalitis is estimated to affect approximately 4 people per 100,000 per year. Microglia are professional antigen presenting cells that are capable of crosstalk with T cells to coordinate the antiviral response. However, microglia also express inflammatory effectors that can contribute to neuropathology. Parsing critical antiviral functions versus neuropathological functions of microglia and CSF1R signaling will be important to improve interventions for viral encephalitis.

Design/Methods Using Theiler’s murine encephalomyelitis virus (TMEV) in acute and chronic neurotropic infection models and PLX5622, a CSF1R inhibitor that depletes microglia in the CNS, we probed the contribution of the CSF1R-microglia axis to the CNS antiviral response.

Results We find that CSF1R-mediated microglia depletion in an acute infection model results in fatal encephalitis. These mice have no hinderance of immune cell infiltration into the CNS, however, the expression of antigen presentation machinery was decreased in myeloid cells and proinflammatory pathways were upregulated in CNS T cells. Surprisingly, CSF1R-mediated microglia depletion in chronic TMEV infection does not result in acute fatal encephalitis. Instead, long-term CSF1R inhibition exacerbates TMEV-induced demyelination and was associated with immunosuppression in the CNS and splenic compartments. This phenotype was partially reversible by discontinuing CSF1R inhibition.

Conclusions

The CSF1R-microglia axis is a critical node in the response to neurotropic picornavirus infection that varies depending on the host strain. In acute TMEV infection, the CSF1R-microglia axis is critical to regulate a robust antiviral response. In chronic TMEV infection, the CSF1R-microglia axis is necessary to stimulate a tepid antiviral response.

Authors/Disclosures
John Michael Sanchez (University of Utah) PRESENTER	Mr. Sanchez has nothing to disclose.
	No disclosure on file
	No disclosure on file
Tyler J. Hanak (University of Utah Department of Pathology)	Mr. Hanak has received personal compensation for serving as an employee of Nuvasive Clinical Services.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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Abstract Details