Vaginal transmission causes prolonged Zika virus shedding in the vaginal mucosa and delays systemic dissemination.

Zika virus (ZIKV) has emerged as a significant health threat worldwide. Although typically mosquito-borne, recent evidence suggests that ZIKV is also a sexually transmitted virus. While persistent ZIKV infections in male reproductive tissues have been identified, little is understood regarding the outcomes of primary sexual transmission in females. We investigated how the route of infection affects vaginal ZIKV shedding and dissemination. In two mouse models, vaginal infection resulted in prolonged ZIKV shedding in the vaginal mucosa with delayed systemic infection. Furthermore, heightened vaginal inflammation did not influence ZIKV replication or dissemination, in contrast to previous studies of mosquito-borne infection. Thus, vaginal infection significantly alters ZIKV infection kinetics and must be considered when developing novel treatments.

Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity.

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.

The Application of Humanized Mouse Models for the Study of Human Exclusive Viruses.

The symbiosis between humans and viruses has allowed human tropic pathogens to evolve intricate means of modulating the human immune response to ensure its survival among the human population. In doing so, these viruses have developed profound mechanisms that mesh closely with our human biology. The establishment of this intimate relationship has created a species-specific barrier to infection, restricting the virus-associated pathologies to humans. This specificity diminishes the utility of traditional animal models. Humanized mice offer a model unique to all other means of study, providing an in vivo platform for the careful examination of human tropic viruses and their interaction with human cells and tissues. These types of animal models have provided a reliable medium for the study of human-virus interactions, a relationship that could otherwise not be investigated without questionable relevance to humans.