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The Role of CXCL9 in Genital HSV-2 Infection

CXCL9 在生殖器 HSV-2 感染中的作用

基本信息

批准号：
7624586
负责人：
DANIEL J CARR
金额：
$ 28.64万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7624586
关键词：
Acute Address Adenoviruses Adoptive Transfer American Animals Brain Stem CXC chemokine receptor 3 CXCL10 gene CXCL9 gene CXCR3 gene Cell physiology Cells Cellular Infiltration Characteristics Child Chimera organism Clinical Congenic Mice Congenital herpes simplex Dendritic Cells Disease Epidemiologic Studies Female Gene Transfer Genital system Goals Health Human Human Herpesvirus 2 Immune response Immunocompromised Host Incidence Individual Infection Infection Control Interferon Type II Latent Virus Learning Leukocyte Trafficking Ligands Low income Lymphocyte Modeling Mothers Mus Natural Killer Cells Nature Newborn Infant Predisposition Prevalence Production Proteins Race Recurrence Research Personnel Resistance Role Sentinel Sexually Transmitted Diseases Simplexvirus Small Inducible Cytokine B9 Spinal Cord Spleen T-Cell Activation T-Lymphocyte T-Lymphocyte and Natural Killer Cell Testing Tissues Transgenic Mice United States Vaccines Vagina Viral Viral Drug Resistance Viral Load result Virus Virus Diseases Virus Shedding Wild Type Mouse Woman base cell motility chemokine chemokine receptor cytokine genital herpes genital infection lymph nodes mouse model outreach program pathogen programs receptor sex sexually active therapeutic development trafficking university student

项目摘要

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.

描述（由申请人提供）： 2 型单纯疱疹病毒 (HSV-2) 等性传播疾病对于其他方面健康的女性来说是一个严重问题。每年新增生殖器 HSV 感染病例数接近 50 万，估计有 40-6000 万美国人感染该病毒。 HSV-2 感染在免疫功能低下的个体和新生儿中尤其严重。在美国，与 HSV-2 流行率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教育推广计划而下降。根据这些结果，HSV-2 仍然是美国的一个主要健康问题。由于感染的性质，我们开发了一种小鼠模型，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相关的具体问题。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。我们建议通过测试以下假设来进一步表征这些初步观察结果：CXCL9、CXCL10 和 CXCR3 通过促进阴道组织、脊髓和/或脑干内激活的 T 细胞和 NK 细胞的募集和功能，在控制生殖器 HSV-2 感染中至关重要。为了检验这一假设，我们计划使用趋化因子受体 CXCR3 表达缺陷、配体 CXCL9 或 CXCL10 缺陷的小鼠，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受感染组织中的传播有关。在完成这项研究的过程中，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，并在此过程中促进治疗策略（例如疫苗或基因转移）的开发，以降低感染的发生率或降低潜伏病毒重新激活的能力。