Microglia are critical in activating cytotoxic T cells during West Nile virus encephalitis

Identification: Funk, Kristen

Microglia are critical in activating cytotoxic T cells during West Nile virus encephalitis
Kristen E. Funk and Robyn S. Klein
Washington University, St. Louis, MO
Microglia are the resident immune cells of the central nervous system (CNS), however, their role during viral infection of the CNS is not entirely clear. We hypothesize that microglia help control the initial viral infection, then act as the antigen presenting cells in the CNS, necessary to recruit and locally restimulate T lymphocytes, which clear the virus. To test this hypothesis, we used PLX5622, an antagonist to colony stimulating factor 1 receptor (CSF1R), provided in standard mouse chow. After two weeks of PLX5622 treatment, microglia are depleted by about 90%. Mice depleted of microglia succumb to peripheral infection of the virulent strain of West Nile virus (WNV-NY99) significantly more than mice fed control chow. This is accompanied by increased viral burden within the CNS; however, there is also significant loss of virologic control in peripheral organs. In order to determine whether CNS infection is sufficient to cause the survival phenotype, mice were infected with an attenuated strain of WNV (NS5-E218A) via intracranial inoculation. Attenuation of this virus allows for more efficient targeting by innate immune mechanisms that limit peripheral organ infection. Depletion of microglia prior to intracranial infection with WNV-NS5-E218A increases mortality from 20% to 70%. To determine whether this may be due to deficient recruitment and activation of T lymphocytes within the CNS, flow cytometry was performed on CNS immune cells following intracranial infection of WNV-NS5-E218A. Results show that microglial depletion does not reduce recruitment of adaptive immune cells, but that these cells lack full activation. Flow cytometry analysis suggests that microglia are critical to supply costimulatory signal 2 for T cell activation. Together, these data indicate that microglia are critical in the adaptive immune response that protects the CNS from fatal viral encephalitis.
This work is supported in part by 1K99 AG053412 to KEF.


Credits: None available.