The Role of CXCL9 in Genital HSV-2 Infection

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DESCRIPTION (provided by applicant): Sexually transmitted diseases such as herpes simplex virus type 2 (HSV-2) are a significant problem in otherwise healthy women. The number of new cases of genital HSV infection is approaching 500,000 individuals annually with an estimated 40-60 million Americans infected with the virus. HSV-2 infections are particularly severe in immunocompromised individuals and newborns. Demographic characteristics associated with increased HSV-2 prevalence in the USA include female sex, race, lower eductional level, and lower income. Likewise, there does not appear to be a decrease in the incidence of HSV-2 as a result of educational outreach programs even among college students. Based on these results, HSV-2 continues to be a major health problem within the United States. Due to the nature of the infection, a mouse model has been developed in which specific questions related to pathogenic manifestations associated with the infection and the host immune response to the virus can be addressed. We have taken advantage of this model to initiate a study investigating the role of chemokines in the host response to infection. We have found one group of chemokines including monokine induced by interferon-gamma (CXCL9) and interferon gamma-inducible protein 10 (CXCL10) to be expressed in selective tissues post genital HSV-2 infection. Preliminary results have also found mice deficient in the lone receptor for these chemokines, CXCR3, to be highly susceptible to genital infection. We propose to further characterize these initial observations by testing the hypothesis that CXCL9, CXCL10, and CXCR3 are crucial in the control of genital HSV-2 infection by facilitating the recruitment and function of activated T cells and NK cells within the vaginal tissue, spinal cord, and/or brain stem. To test this hypothesis, we plan on using mice deficient in the expression of the chemokine receptor CXCR3, deficient in the ligands CXCL9 or CXCL10, or chimeric and transgenic mice infected with a clinical isolate of HSV-2 to characterize the host immune response to the virus as it relates to virus titer and spread in the infected tissue. In accomplishing this study, it is anticipated we will learn the role of these sentinel chemokines in orchestrating a protective host response to infection and in so doing, facilitate the development of therapeutic strategies (e.g., vaccine or gene transfer) to reduce the incidence of infection or reduce the capacity of latent virus to reactivate.