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.

单纯疱疹病毒类型2（HSV-2）感染是终生的，是生殖器溃疡疾病的主要原因 遍布。生殖器HSV-2重新激活的临床结果从完全无症状到 频繁和严重的生殖器溃疡发生不频繁和短暂的复发：原因是可变性的原因 不知道。使用人类志愿者的生殖器皮肤和粘膜活检，我们表明 HSV-2重新激活导致局部免疫反应的长期持久性。 CDS T细胞持续 皮肤表皮连接（DEJ）连续与释放病毒体的感觉神经末端相连。这 独特的解剖分布表明，局部CDS T细胞可能在快速遏制中起关键作用 外围病毒感染，从而使HSV-2疾病的临床和病毒学病程充气 人类。在上一个赠款周期中，我们开发了一个细胞类型的特异性激光捕获微分解（LCM） 分离单个CDS T细胞并测量其活性的方法。通过使用合并的方法 CDS特异性LCM，整个基因组转录分析和TCR曲目深度测序，我们现在可以 阐明组织驻留记忆CD T细胞与生殖器疱疹疾病严重程度之间的关联 人类。在这个项目中，我们将研究HSV-2疾病严重程度与数量之间的关联， 以前HSV-2复发部位的组织驻留记忆CD T细胞的质量和多样性 人类。我们的具体目的是：1）定义解剖分布，密度，衰减动力学和 组织驻留记忆CD T细胞的抗病毒特征基因在轻度与参与者中不同 严重的生殖器HSV-2疾病； 2）定义T细胞受体（TCR）曲目动力学和 组织驻留记忆CD T细胞的抗原特异性与生殖器疱疹有关 严重程度。我们将从具有不同疾病结局的患者队列中获得顺序的活检组织：轻度 疾病，定义为每年复发率<2次发作，而重复疾病的复发率> 6 每年情节。该项目将定义成功的周围免疫反应的特征 HSV-2可以作为疫苗开发过程中免疫力的潜在相关性。 相关性（请参阅说明）： 生殖器疱疹影响美国人口的17％；没有治疗或疫苗可用。我们不知道为什么有些 患有这种感染的人患有严重的疾病，而其他人则非常温和。我们已经开发了新的实验室 研究来自生殖器疱疹的人的样品中的免疫细胞的方法，我们将适用于理解 为了开发有效的疫苗，患有轻度和重度疾病的人之间的差异。