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Abstract Although many viral infections are linked to the development of neurological disorders, the mechanism governing virus-induced neuropathology remains poorly understood, particularly when the virus is not directly neuropathic. Using a mouse model of Zika virus (ZIKV) infection, we found that the severity of neurological disease did not correlate with brain ZIKV titers, but rather with infiltration of bystander activated NKG2D+CD8+ T cells. Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis, suggesting that CD8+ T cells induce neurological disease independent of TCR signaling. Furthermore, spleen and brain CD8+ T cells exhibited antigen-independent cytotoxicity that correlated with NKG2D expression. Finally, viral infection and inflammation in the brain was necessary but not sufficient to induce neurological damage. We demonstrate that CD8+ T cells mediate virus-induced neuropathology via antigen-independent, NKG2D-mediated cytotoxicity, which may serve as a therapeutic target for treatment of virus-induced neurological disease.

Following the recent outbreak of Zika virus (ZIKV) infections in Latin America, ZIKV has emerged as a global health threat due to its ability to induce neurological disease in both adults and the developing fetus. ZIKV is largely mosquito-borne and is now endemic in many parts of Africa, Asia, and South America. However, several reports have demonstrated persistent ZIKV infection of the male reproductive tract and evidence of male-to-female sexual transmission of ZIKV. Sexual transmission may broaden the reach of ZIKV infections beyond its current geographical limits, presenting a significant threat worldwide. Several mouse models of ZIKV infection have been developed to investigate ZIKV pathogenesis and develop effective vaccines and therapeutics. However, the majority of these models focus on mosquito-borne infection, while few have considered the impact of sexual transmission on immunity and pathogenesis. This review will examine the advantages and disadvantages of current models of mosquito-borne and sexually transmitted ZIKV and provide recommendations for the effective use of ZIKV mouse models.