Immunogenetic determinants of HSV-2 infection and disease

HSV-2 感染和疾病的免疫遗传学决定因素

• 批准号: 10004983
• 负责人: Jennifer M Lund
• 金额: $ 27.66万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004983
• 关键词: Acyclovir; Adoptive Transfer; Affect; Alleles; Antiviral Agents; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Communicable Diseases; Cues; Data; Dendritic Cells; Development; Disease; Disease Outcome; Equilibrium; Exposure to; Frequencies; Ganglia; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genetic Variation; Genital system; Herpesvirus 1; Heterogeneity; Human; Human Herpesvirus 2; Immune; Immune response; Immune system; Immunity; Immunogenetics; Immunotherapeutic agent; Inbred Strains Mice; Individual; Infection; Infection prevention; Inflammation; Kinetics; Knowledge; Lead; Lesion; Life; Link; Location; Lymphoid; Lymphoid Tissue; Memory; Modeling; Mouse Strains; Mucosal Immune Responses; Mucous Membrane; Mus; Natural Immunity; Natural Killer Cells; Nervous system structure; Neuraxis; Neurons; Patients; Phase; Phenotype; Play; Population; Predisposition; Prevention; Prevention strategy; Preventive vaccine; Public Health; Quantitative Trait Loci; Recombinants; Recurrence; Regulation; Regulatory T-Lymphocyte; Role; Sensory Ganglia; Severity of illness; Sexually Transmitted Diseases; Simplexvirus; Site; Skin; Stress; Surface; Susceptibility Gene; T memory cell; T-Lymphocyte; Therapeutic; Time; Tissues; Ulcer; Vaccines; Vagina; Variant; Viral; Virus; Virus Diseases; Virus Shedding; West Nile viral infection; Work; adaptive immunity; base; cervicovaginal; chronic infection; design; disease phenotype; experimental study; genital herpes; genomic locus; human disease; immune activation; improved; interest; lifestyle factors; macrophage; microbial; monocyte; mortality; mouse model; neurotropic; neutrophil; novel; pathogen; pathogenic virus; phenotypic data; prevent; reproductive tract; response; treatment strategy

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.

项目摘要 生殖器单纯疱疹病毒2型（HSV-2）感染是终身的，目前没有治愈或预防措施 疫苗，尽管付出了巨大的努力。此外，目前的抗病毒药物如阿昔洛韦不能完全消除 所有患者的病毒脱落或症状性生殖器溃疡，强调需要新的预防措施， 治疗策略有症状和无症状的脱落率存在相当大的差异， 以及症状性疾病之间的HSV感染的个人，但很少了解的原因， 这种可变性。据推测，环境和生活方式的因素，如压力，以及遗传 因素可能发挥作用。因此，我们建议使用协作交叉与小鼠模型， 阴道HSV-2感染，以揭示与HSV-2脱落和疾病相关的新遗传区域，以及 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，我们希望为识别和随后的 开发新的宿主靶向和/或基于免疫的HSV治疗和预防策略， 减轻这种全球性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）是一个具有高水平站立能力的重组近交系小鼠种群。 遗传变异，并被设计为允许研究一个或多个基因中的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 在西尼罗病毒感染易感性和疾病以及免疫表型。我们现建议 利用我们在CC和HSV-2小鼠模型方面的专业知识，对CC小鼠进行筛选 用于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的病毒靶点的组织部位内的免疫应答表型， 如生殖道和中枢神经系统（CNS）。我们将利用这些数据来进行数量性状基因座 (QTL)定位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间的反应， 时间和感染后的不同组织中。通过这项拟议的工作，我们希望确定新的HSV 易感性等位基因，可以为宿主靶向HSV治疗和预防的合理设计提供信息 战略布局此外，越来越多的人认识到免疫细胞表型和功能可以广泛变化 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节。