The long term objective of the proposed research is to further our understanding of mucosal immunity in the female genital tract, especially as it relates to protection against sexually-transmitted diseases and to immunocontraception.
Specific aims are as follows:
Aim 1. to establish an adult mouse model suitable for studies of the role of mucosal immunity in protection against vaginal herpes simplex virus type 2 (HSV-2) infection. This will be done by demonstrating that ovarian hormones influence vaginal HSV-2 infection, that adult mice can be made uniformly susceptible to infection by treatment with estradiol followed by DepoProvera, and that vaginal infection by an attenuated strain of HSV-2 elicits immunity that later prevents infection of vaginal epithelium by challenge virus.
Aim 2. to obtain basic information about immune responses to vaginal infection by HSV-2. This will include: the number and distribution of Langerhans cells, macrophages, T cells, B cells and plasma cells in the vagina; the occurrence and distribution of cells producing the anti-viral cytokines, interferon gamma and tumor necrosis factor alpha; and the presence of HSV-2 specific lgA and IgG antibodies in the vaginal fluids of immune mice.
Aim 3. to test several hypotheses concerning immune mechanisms responsible for protection against challenge infection. In particular, we will: a) use specific depletion of T cells in vivo to determine whether these cells are involved in the immunity that preVents infection of the vaginal epithelium; b) use passive transfer of antibody to determine whether virus-specific IgG prevents infection of the vaginal epithelium; c) determine whether reduced antibody titers in vaginal secretions are correlated with increased infection of vaginal epithelium, and whether infection of the nervous system is correspondingly increased; and d) if mice in (c) exhibit infection of vaginal epithelium but are still immune to infection of the nervous system, we will use specific depletion of cytotoxic T cells in vivo to determine whether they are involved in a second line of immune defense that prevents spread of challenge virus to the nervous system.
Aim 4. to determine whether parenteral immunization, which elicits both IgG and cytotoxic T cell immunity, can protect against vaginal HSV-2 infection in the adult mouse model.
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