Exploring mechanisms of bystander T cell activation in off-target neuropathology during Zika virus infection

Zika virus (ZIKV) is an emerging mosquito-borne and sexually transmitted virus. The most recent South American epidemic in 2015-2016 identified several devastating effects of ZIKV infections. These include the development of microcephaly in growing fetuses and paralysis in adults. ZIKV has become a continued health threat in Latin America, Africa, and Southeast Asia through both mosquito-borne and sexual transmission, but there are currently no vaccines or treatments. Normally, CD8+ T cells should target and kill ZIKV-infected cells while leaving healthy cells alone. In our mouse model of ZIKV infection, we identified CD8+ T cells that become highly activated and kill non-infected cells in the brain, resulting in paralysis. In this project, we will examine how these T cells become excessively activated and cause off-target neurological damage. Specifically, we will investigate how inflammation and metabolism in the brain influence CD8+ T cell activation and off-target killing. We will also assess the role of immune cells in the brain, called microglia, in creating these dangerous inflammatory conditions. After determining how these T cells are activated, we will investigate methods to treat and prevent CD8+ T cells from causing off-target brain damage during ZIKV infection. As CD8+ T cells are thought to cause damage in other neurological diseases, like multiple sclerosis, the mechanisms we discover may be applicable to other diseases. Thus, our research will uncover mechanisms of T cell-mediated neurological diseases and identify novel treatment strategies.