Mucosal immune responses in the murine female genital tract against intravaginal infection with herpes simplex virus type-2

Although the genital tract is the main portal of entry for sexually transmitted infections in women, we still have limited understanding of the immune responses in the local tissue and the factors that impact their generation. Genital herpes is the most common sexually transmitted infection in the world; affecting close to one tenth of the global population. There is as yet no cure and close to a century of research has failed to produce an efficacious vaccine for prevention of genital herpes. Clearly there is still much to learn about this disease and the host immune responses associated with its protection. The studies presented here encompass two projects examining genital mucosal immune responses against herpes simplex virus type-2 infection. In the first project, we investigated the effects of female sex hormones estradiol and progesterone on the immune responses generated against genital infection with herpes simplex virus type-2. This study further demonstrated the importance of local hormone environment in both the susceptibility to genital infection and the type of immune responses generated. Progesterone induced susceptibility while estradiol prevented infection. Hormone status at the time of immunization resulted in qualitative differences in the type of protective immune responses elicited during secondary virus challenge. The second project focused on the role of the genital mucosa and tissue memory CD8+T cell responses against genital herpes infection. Our results show that a high frequency of virus-specific effector memory CD8+T cells is found in the genital tissue in comparison to lymphoid organs after clearance of primary herpes infection. We demonstrate that genital virus-specific memory T cells playa central role in mediating protection against intravaginal infection. Furthermore, we report that protective responses against genital herpes can be generated at the mucosa; in the absence of secondary lymphoid organs. In the absence of lymph nodes and spleen, memory CD8+ T cells are found in the genital tissue long after primary infection and these cells are activated in the genital mucosa upon secondary infection. Lastly, we explored the requirements for activation of memory CD8+ T cells in the genital tissue. Activation of memory CD8+ T cells in the genital tissue does not require antigen presentation by haematopoietic dendritic cells. Together, these findings highlight the importance of the local tissue environment at the site of infection, as well as shed new light on the functional role of the genital mucosa and tissue memory T cells in response to sexually transmitted infections.