Genital mucosal DC: Herpes simplex virusIntestinal
DC: Salmonella typhimuriumLung Influenza Infection |
Laboratory
Genital mucosal DC: Herpes simplex virusIntestinal
DC: Salmonella typhimuriumLung Influenza Infection |
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Genital
mucosal DC: Herpes simplex virus
One of the laboratory's major interests is to understand the mechanism of immune induction at the natural route of infection to herpes simplex virus (HSV) type 2 infection. HSV-2 is one of the most common sexually transmitted diseases with a prevalence of approximately 45 million in the United States. Currently, the mechanism for immune induction to HSV-2 in the genital mucosa is unknown. The examination of the immune responses induced in the female genital tract must take into account that, unlike other mucosal surfaces, it undergoes hormone-dependent changes over the course of the estrous cycle. Thus, our laboratory is currently studying the dendritic cells within the vaginal mucosa and comparing their phenotype, localization and function at different estrous stages in order to understand the mechanism of immune induction at this special site. A key question in this regard relates to the role of the antigen-presenting cells, particularly, the dendritic cells. Mice are susceptible to genital HSV-2 infection only during the diestrous phase. We have found a previously unanticipated role of submucosal dendritic cells in Th1 induction to herpes simplex virus-2 infection in the progesterone-dominant female mice. We showed that HSV-2 is recognized by the innate pattern recognition receptor, Toll-like receptor 9 (TLR9). In addition to direct activation by patter recognition receptors, we showed that DCs require TLR-dependent instructive signals from the infected cells in order to induce differentiation of effector T cells. We further demonstrated the requirement for TLR-dependent signal in enabling maximum screening of cognate lymphocytes during initiation of adaptive immunity through remodeling of the lymph node arteriole. These studies collectively demonstrated the importance of tissue-DC interaction in the initiation of antiviral immunity. Our current and future goals are to understand 1) how infected stromal cells instruct the immune system to induce antiviral Th1 responses, 2) how dendritic cells in the vagina instruct effector T cells to migrate back to the vaginal mucosa to elicit protection, 3) how the effector and memory CD4 and CD8 T cells provide protection within the vaginal mucosa, and 4) how we can use the information obtained from our collective effort to make an effective prophlactic vaccine against the spread of HSV-2. We hope that by understanding the mechanism of immune generation to HSV-2 we will be able to design effective vaccines against HSV and other sexually transmitted disease agents.
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