Investigating the Role of Microglia in ZIKV-induced Neuropathology

Zika virus (ZIKV) is a mosquito borne Flavivirus that has caused several outbreaks across Asia, Africa, and South America. ZIKV infections have been associated with severe neurological disease, such as Guillain-Barr; Syndrome and microcephaly. Currently, the mechanisms of ZIKV-induced neurological disease are poorly understood, hindering the ability to develop effective therapeutics and preventative measures. In our established model of ZIKV infection, mice exhibit high viral load in their brains during infection as well as symptoms of neurological disease including hind-limb paralysis and weakness. We have established that these neurological symptoms are mediated by NKG2D receptors on infiltrating CD8+ T cells in the brain. NKG2D ligands (NKG2DL) are upregulated during instances of cell stress such as neuroinflammation caused by microglia, which are resident macrophages of the central nervous system and act as first responders to viral infection. To determine whether microglia contribute to ZIKV-induced neuropathology, we will deplete them using a Colony Stimulating Factor 1 Receptor (CSF1-R) inhibitor, PLX3397, and determine whether it has a protective effect against hindlimb paralysis. Further investigation will determine how microglia play a role in NKG2D-mediated cytotoxicity. We plan to conduct a multiplex cytokine array analysis from the brains of microglia-depleted mice to identify their contributions to neuroinflammation. We will also use immunofluorescence microscopy to determine whether microglia promote NKG2DL expression and assess its colocalizes with markers of neuronal damage. These findings will elucidate the critical role of microglia-T cell interactions in virus-induced neurological disease and provide avenues for development of novel therapies.