The Role of CXCL9 in Genital HSV-2 Infection

描述(申请人提供)：性传播疾病，如单纯疱疹病毒2型(HSV-2)，在其他健康的女性中是一个严重的问题。每年生殖器单纯疱疹病毒感染的新病例数量接近50万人，估计有4000万至6000万美国人感染了这种病毒。HSV-2感染在免疫功能低下的个人和新生儿中尤为严重。在美国，与HSV-2流行增加相关的人口特征包括女性、种族、较低的教育水平和较低的收入。同样，即使在大学生中，HSV-2的发病率似乎也没有因为教育推广计划而下降。根据这些结果，HSV-2仍然是美国境内的一个主要健康问题。由于感染的性质，已经开发了一种小鼠模型，在该模型中可以解决与感染相关的致病表现和宿主对病毒的免疫反应的特定问题。我们利用这个模型启动了一项研究，调查趋化因子在宿主对感染的反应中的作用。我们发现一组趋化因子，包括干扰素-γ诱导的单核细胞因子(CXCL9)和干扰素-γ诱导蛋白10(CXCL10)在生殖器HSV-2感染后的选择性组织中表达。初步结果还发现，缺乏这些趋化因子的唯一受体CXCR3的小鼠非常容易受到生殖器感染。我们建议通过检验CXCL9、CXCL10和CXCR3在生殖器HSV-2感染的控制中起关键作用的假设来进一步表征这些初步观察结果，该假设通过促进激活的T细胞和NK细胞在阴道组织、脊髓和/或脑干中的招募和功能来实现。为了验证这一假设，我们计划使用缺乏趋化因子受体CXCR3表达的小鼠、缺乏CXCL9或CXCL10配体的小鼠，或感染HSV-2临床分离株的嵌合和转基因小鼠来表征宿主对病毒的免疫反应，因为它与病毒滴度和在感染组织中的传播有关。在完成这项研究时，预计我们将了解这些前哨趋化因子在协调宿主对感染的保护性反应中的作用，并在这样做的过程中，促进治疗策略的发展(例如，疫苗或基因转移)，以减少感染的发生率或降低潜伏病毒重新激活的能力。

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.