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: 10171556
• 负责人: Jennifer M Lund
• 金额: $ 1.17万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171556
• 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; Genitalia; 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 生殖器疱疹病毒2（HSV-2）的感染是终身的，目前尚无治愈或预防性 尽管做出了巨大努力，疫苗。此外，当前的抗病毒药物（如阿辛克罗维尔）无法完全消除 所有患者的病毒脱落或有症状的生殖性溃疡，强调了新的预防和 治疗策略。有症状和无症状的脱落率有很大差异 以及HSV感染的个体之间有症状的疾病，但对基本原因的理解很少 这种变异性。假设环境和生活方式因素（例如压力）以及遗传 因素可以扮演角色。因此，我们建议将协作交叉与鼠标模型一起使用 阴道HSV-2感染以发现与HSV-2脱落和疾病相关的新遗传区域 与组织特异性的免疫反应一样。通过定义调节这些的寄主遗传区域 感染和与疾病相关的表型，我们希望为识别和随后的途径铺平道路 开发新颖的宿主靶向和/或基于免疫的HSV疗法和预防策略 减轻了这种全球传染病的负担以及通过粘膜表面传播的其他感染。 协作十字架（CC）是一个重组近交小鼠菌株的人群，具有高水平的站立 遗传变异，旨在允许研究一个或 更多的基因和感兴趣的表型。我们已经成功使用了CC筛选涉及的遗传基因座 在西尼罗河病毒感染易感性和疾病以及免疫表型中。我们现在建议 利用CC以及HSV-2的鼠标模型来执行我们的专业知识来执行CC鼠标的屏幕 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 淋巴组织和组织部位中的免疫反应表型，这些病毒是疾病的病毒靶标的 作为生殖道和中枢神经系统（CNS）。我们将使用这些数据执行定量性状基因座 （QTL）映射以识别与阴道病毒脱落率和水平相关的染色体区域 相关疾病，例如生殖器病变和死亡率的形成，以及不同的免疫细胞反应 感染后的时间和不同的组织。通过这项拟议的工作，我们希望确定新颖的HSV 可以为宿主靶向的HSV治疗和预防的合理设计提供理性设计的敏感性等位基因 策略。此外，越来越多地认识到免疫细胞表型和功能可能会变化很大 基于组织位置。这项研究将确定与感染免疫反应有关的遗传区域 在不同的组织位置，包括淋巴机和粘膜组织，以增加对宿主的了解 感染后组织特异性免疫细胞功能的遗传调节。