Correlating HSV-2 Disease Severity with Tissue Resident CD8 T-cells

将 HSV-2 疾病严重程度与组织驻留 CD8 T 细胞相关联

• 批准号: 8696991
• 负责人: Jia Zhu
• 金额: $ 24.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8696991
• 关键词: Affect; Anatomic Sites; Anatomy; Animal Model; Antigenic Specificity; Antigens; Antiviral Agents; Biopsy; Blood; Blood Vessels; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Survival; Cells; Characteristics; Clinical; Clinical Research; Collaborations; Confocal Microscopy; Containment; Dermal; Dermis; Disease; Disease Outcome; Exhibits; Frequencies; Funding; Genes; Genital system; Genome; Goals; Grant; Herpesvirus 1; Human; Human Herpesvirus 2; Human Volunteers; Immune; Immune response; Immunity; Immunologic Surveillance; In Situ; Individual; Infection; Kinetics; Knowledge; Laboratories; Lesion; Lytic; Measures; Memory; Messenger RNA; Metabolic; Metabolism; Methods; Mucosal Immunity; Mucous Membrane; Mus; Outcome; Participant; Pathogenesis; Patients; Peripheral; Physiological; Play; Population; Positioning Attribute; Property; Proteins; Recurrence; Role; Sampling; Sensory Nerve Endings; Severity of illness; Simplexvirus; Site; Skin; Study models; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Tissues; Ulcer; Vaccine Design; Vaccines; Vaccinia Virus Study; Viral; Virion; Virus; Virus Diseases; cell type; chemokine; clinical epidemiology; cohort; complementarity-determining region 3; cytokine; deep sequencing; density; genital herpes; human data; human tissue; in vivo; insight; laser capture microdissection; particle; pathogen; reactivation from latency; response; spatiotemporal; vaccine development

Herpes simplex virus type-2 (HSV-2) infections are lifelong, and a leading cause of genital ulcer disease worldwide. The clinical outcome of genital HSV-2 reactivation varies widely from completely asymptomatic to infrequent and short-lasting recurrences to frequent and severe genital ulcerations: reasons for this variability are not known. Using biopsies of genital skin and mucosa from human volunteers, we have shown that HSV-2 reactivation results in a long-term persistence of local immune responses. CD8 T cells persist at the dermal-epidermal junction (DEJ) contiguous to the sensory nerve endings where virions are released. The unique anatomical distribution suggests that local CDS T cells might play a pivotal role in rapid containment of viral infection in the periphery, thus influencing the clinical and virologic course of HSV-2 disease in humans. In the last grant cycle, we developed a cell-type specific laser capture microdissection (LCM) method to isolate individual CD8 T cells in situ and measure their activity. By using combined approaches of CD8-specific LCM, whole genome transcriptional profiling and TCR repertoire deep sequencing, we can now elucidate associations between tissue resident memory CD8 T cells and genital herpes disease severity in humans. In this project, we will investigate the association between HSV-2 disease severity and the quantity, quality and diversity of tissue resident memory CD8 T cells at the site of previous HSV-2 recurrence in humans. Our specific aims are: 1) to define whether the anatomic distribution, density, decay kinetics and the antiviral signature genes of tissue resident memory CD8 T cells differ in participants with mild versus severe genital HSV-2 diseases; 2) to define whether the T cell receptor (TCR) repertoire dynamics and antigenic specificity of tissue resident memory CD8 T cells are associated with genital herpes disease severity. We will obtain sequential biopsy tissues from patient cohorts with distinct disease outcomes: mild disease, defined as recurrence rate < 2 episodes per year and severe disease as recurrence rate > 6 episodes per year. This project will define the characteristics of a successful peripheral immune response to HSV-2 that can be harnessed as a potential correlate of immunity during vaccine development.

单纯疱疹病毒2型(HSV-2)感染是终生的，也是生殖器溃疡疾病的主要原因 全世界。生殖器HSV-2重新激活的临床结果差异很大，从完全无症状到 罕见且持续时间短的频繁和严重生殖器溃疡复发：这种变异的原因 都是未知的。使用来自人类志愿者的生殖器皮肤和粘膜的活检，我们已经证明了HSV-2的重新激活导致了局部免疫反应的长期持续。CD8 T细胞在 真皮-表皮交界处(DEJ)，与释放病毒粒子的感觉神经末梢相连。这个 独特的解剖分布表明，局部CDS T细胞可能在快速遏制中发挥关键作用 病毒感染在外围，从而影响HSV-2病的临床和病毒学病程 人类。在上一个资助周期中，我们开发了细胞型特定激光捕获显微切割(Lcm)。 方法原位分离单个CD8T细胞并测定其活性。通过使用组合的方法 CD8特异性LCM，全基因组转录图谱和TCR谱系深度测序，我们现在可以 组织驻留记忆CD8 T细胞与生殖器疱疹疾病严重程度的关系 人类。在这个项目中，我们将研究人类HSV-2复发部位组织驻留记忆CD8 T细胞的数量、质量和多样性与HSV-2疾病严重程度之间的关系。 我们的具体目标是：1)确定组织驻留记忆CD8 T细胞的解剖分布、密度、衰变动力学和抗病毒特征基因在轻、重度生殖器HSV-2疾病患者中是否有所不同；2)确定组织驻留记忆CD8 T细胞的T细胞受体(TCR)谱动态和抗原特异性是否与生殖器疱疹疾病的严重程度相关。我们将从患者队列中获得不同疾病结局的连续活检组织：轻度疾病定义为复发率每年2次，重度疾病定义为复发率每年6次。该项目将确定对HSV-2成功的外周免疫反应的特征，这些特征可在疫苗开发期间被用作潜在的免疫相关因素。