Immunogenetic determinants of HSV-2 infection and disease

项目总结 生殖器单纯疱疹病毒-2(HSV-2)感染是终生的，目前还没有治愈或预防的方法 尽管付出了很大努力，但还是接种了疫苗。此外，目前的抗病毒药物，如阿昔洛韦，并不能完全消除 所有患者的病毒脱落或有症状的生殖器溃疡，强调了新的预防和治疗的必要性 治疗策略。有症状和无症状的脱落率有很大的差异。 以及单纯疱疹病毒感染者之间的症状性疾病，但对背后的原因了解很少 这种可变性。据推测，环境和生活方式因素，如压力，以及遗传 因素可能会发挥作用。因此，我们建议将协作交叉与小鼠模型结合使用 阴道感染HSV-2以发现与HSV-2脱落和疾病相关的新基因区域 与对感染的组织特异性免疫反应一样。通过定义宿主基因区域来调节这些 感染和疾病相关的表型，我们希望为鉴定和后续的研究铺平道路 开发新的宿主靶向和/或基于免疫的单纯疱疹病毒疗法和预防策略， 减轻这一全球传染病以及通过粘膜表面传播的其他感染的负担。 合作杂交(CC)是具有高水平地位的重组近交系小鼠品系的群体 遗传变异，旨在允许研究一个或多个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来筛选涉及的遗传基因座 在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鼠标筛选 HSV-2脱落型、疾病和组织炎症表型的菌株。此外，我们将评估感染后 淋巴组织和作为病毒目标的组织部位的免疫反应表型，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基因座 (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，如生殖器病变的形成和死亡率，以及免疫细胞在不同时期的反应 感染后不同时间和不同组织中。通过这项拟议的工作，我们希望发现新的HSV 可指导合理设计宿主靶向单纯疱疹病毒治疗和预防的易感等位基因 战略。此外，越来越多的人认识到免疫细胞的表型和功能可以有很大的不同。 根据组织位置。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节。

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.