Immunogenetic determinants of HSV-2 infection and disease

项目概要 生殖器单纯疱疹病毒 2 (HSV-2) 感染是终生的，目前尚无治愈或预防方法 尽管付出了巨大努力，但仍获得了疫苗。此外，目前的抗病毒药物如阿昔洛韦并不能完全消除病毒。 所有患者都出现病毒脱落或有症状的生殖器溃疡，强调需要新的预防和治疗 治疗策略。有症状和无症状的排毒率存在很大差异 以及 HSV 感染者之间的症状性疾病，但对其背后的原因知之甚少 这种可变性。据推测，环境和生活方式因素（例如压力）以及遗传因素 因素可能发挥作用。因此，我们建议将协作交叉与小鼠模型结合使用 阴道 HSV-2 感染，以发现与 HSV-2 脱落和疾病相关的新基因区域 与针对感染的组织特异性免疫反应一样。通过定义调节这些的宿主遗传区域 感染和疾病相关的表型，我们希望为鉴定和后续铺平道路 开发新的针对宿主和/或基于免疫的 HSV 疗法和预防策略， 减轻这种全球传染病以及通过粘膜表面传播的其他感染的负担。 协作杂交 (CC) 是一群具有高水平的重组近交小鼠品系 遗传变异，旨在允许研究一种或多种等位基因变异之间的关联 更多的基因和感兴趣的表型。我们已经成功地使用CC来筛选涉及的遗传位点 西尼罗河病毒感染的易感性和疾病以及免疫表型。我们现在建议 利用我们在 CC 以及 HSV-2 鼠标模型方面的专业知识来执行 CC 鼠标屏幕 HSV-2 脱落、疾病和组织炎症表型的菌株。此外，我们将评估感染后 淋巴组织和作为疾病病毒靶标的组织部位内的免疫反应表型，例如 如生殖道和中枢神经系统（CNS）。我们将使用这些数据来执行数量性状位点 （QTL）作图，以确定与阴道病毒脱落率和水平相关的染色体区域，病毒- 相关疾病，例如生殖器病变的形成和死亡，以及不同时点的免疫细胞反应 感染后的时间和不同组织中。通过这项拟议的工作，我们期望识别出新型 HSV 可以为针对宿主的 HSV 治疗和预防的合理设计提供信息的易感性等位基因 策略。此外，人们越来越认识到免疫细胞表型和功能可能存在很大差异 基于组织位置。这项研究将确定与感染免疫反应相关的遗传区域 在不同的组织位置，包括淋巴组织和粘膜组织，从而增加对宿主的了解 感染后组织特异性免疫细胞功能的遗传调控。

PROJECT SUMMARY Infection with genital Herpes Simplex virus-2 (HSV-2) is life-long, and there is currently no cure or preventative vaccine despite substantial efforts. Furthermore, current anti-viral drugs such as acyclovir do not fully eliminate viral shedding or symptomatic genital ulcers for all patients, underscoring the need for new prevention and therapeutic strategies. There is considerable variation in rates of symptomatic and asymptomatic shedding as well as symptomatic disease between HSV-infected individuals, yet little understanding of the reasons underlying this variability. It is hypothesized that environmental and life-style factors such as stress, as well as genetic factors could play roles. Thus, we propose to use the Collaborative Cross in conjunction with a mouse model of vaginal HSV-2 infection to uncover novel genetic regions associated with HSV-2 shedding and disease, as well as with tissue-specific immune responses to infection. By defining host genetic regions that regulate these infection and disease-related phenotypes, we hope to pave the way for the identification and subsequent development of novel host-targeted and/or immune-based HSV therapies and prevention strategies that could lessen the burden of this global infectious disease as well as other infections transmitted via a mucosal surface. The Collaborative Cross (CC) is a population of recombinant inbred mouse strains with high levels of standing genetic variation, and was designed to allow for studies of the association between allelic variation in one or more genes and a phenotype of interest. We have successfully used the CC to screen for genetic loci involved in West Nile virus infection susceptibility and disease as well as immune phenotypes. We now propose to leverage our expertise with the CC as well as with the mouse model of HSV-2 to perform a screen of CC mouse strains for HSV-2 shedding, disease, and tissue inflammation phenotypes. Further, we will assess post-infection immune response phenotypes within both lymphoid tissues and tissue sites that are viral targets of disease, such as the genital tract and the central nervous system (CNS). We will use this data to perform quantitative trait loci (QTL) mapping to identify chromosomal regions associated with vaginal viral shedding rates and levels, virus- associated disease such as the formation of genital lesions and mortality, and immune cell responses at different times and in different tissues post-infection. Through this proposed work, we expect to identify novel HSV susceptibility alleles that could inform the rational design of host-targeted HSV treatments and prevention strategies. Additionally, it is increasingly recognized that immune cell phenotype and function can vary widely based on tissue location. This study will identify genetic regions associated with immune responses to infection in distinct tissue locations, including both lymphoid and mucosal tissues, to thus increase knowledge of the host genetic regulation of tissue-specific immune cell function following infection.