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: 8565777
• 负责人: Jia Zhu
• 金额: $ 27.66万
• 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/8565777
• 关键词: Affect; Anatomic Sites; Anatomy; Animal Model; Antigenic Specificity; Antigens; Antiviral Agents; Biopsy; Blood; Blood Vessels; CD4 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; Grant; Herpesvirus 1; Human; Human Herpesvirus 2; Human Volunteers; Immune; Immune response; Immunity; Immunologic Surveillance; In Situ; Individual; Infection; Instruction; 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; Viral; Virion; Virus; Virus Diseases; cell type; chemokine; clinical epidemiology; cohort; 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 woridwide. 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 forthis 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. CDS 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 inflijencing 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 CDS T cells in situ and measure their activity. By using combined approaches of CDS-specific LCM, whole genome transcriptional profiling and TCR repertoire deep sequencing, we can now elucidate associations between tissue resident memory CDS 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 CDS 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 CDS 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 CDS 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. RELEVANCE (See instructions): Genital herpes affects 17% of US population; no cure or vaccine is available. We do not know why some people with this infection have severe disease, and others very mild. We have developed new laboratory methods to study immune cells in samples from people with genital herpes that we will apply to understand the difference between people with mild and severe disease in order to develop an effective vaccine.

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 全球范围内。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组织检查，我们已经证明 HSV-2的重新激活会导致局部免疫反应的长期持续。CDS T细胞持续存在于 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，从而推测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CDS T细胞并测定其活性。通过使用组合的方法 CDS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CDS 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，我们将调查HSV-2疾病严重程度与病毒数量的关系， 单纯疱疹病毒2型复发部位组织记忆性CDS T细胞的质量和多样性 人类。我们的具体目标是：1)定义解剖分布、密度、衰变动力学和 组织记忆CDS T细胞的抗病毒特征基因在轻度与非轻度患者中有所不同 严重的生殖器单纯疱疹病毒2型疾病；2)确定T细胞受体(TCR)谱系动态和 组织记忆CDS T细胞的抗原特异性与生殖器疱疹疾病相关 严肃性。我们将从具有不同疾病结果的患者队列中获得连续的活检组织：轻度 疾病，定义为每年2次复发，严重疾病定义为复发率6 每年的剧集。该项目将定义成功的外周免疫反应的特征 HSV-2，可在疫苗开发过程中作为潜在的免疫相关性加以利用。 相关性(请参阅说明)： 生殖器疱疹影响了17%的美国人口；目前还没有治愈方法或疫苗。我们不知道为什么有些人 感染这种疾病的人病情严重，其他人病情很轻。我们开发了新的实验室 方法研究生殖器疱疹患者样本中的免疫细胞，我们将应用这些细胞来了解 为了开发出有效的疫苗，区分轻度和重度疾病的人。