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）感染是终身的，是生殖器溃疡疾病的主要原因 世界范围内。生殖器HSV-2再激活的临床结果差异很大，从完全无症状到 罕见和短暂复发到频繁和严重的生殖器溃疡：这种差异的原因 不知道。使用人类志愿者的生殖器皮肤和粘膜活检，我们已经表明， HSV-2再活化导致局部免疫应答的长期持续。CDS T细胞持续存在于 真皮-表皮连接处（DEJ），邻近释放病毒体的感觉神经末梢。的 独特的解剖学分布表明，局部CDS T细胞可能在快速遏制中发挥关键作用， 的病毒感染的外周，从而influjencing临床和病毒学过程中的HSV-2疾病， 人类在上一个资助周期，我们开发了一种细胞类型特异性激光捕获显微切割（LCM） 方法原位分离单个CDS T细胞并测量其活性。通过采用以下综合办法， CDS特异性LCM、全基因组转录谱分析和TCR库深度测序，我们现在可以 阐明组织驻留记忆CDS T细胞与生殖器疱疹疾病严重程度之间的关系， 人类在这个项目中，我们将研究HSV-2疾病严重程度和数量之间的关系， HSV-2复发部位组织驻留记忆CDS T细胞的质量和多样性 人类我们的具体目标是：1）确定是否解剖分布，密度，衰变动力学和 组织驻留记忆CDS T细胞的抗病毒标记基因在轻度与轻度 严重生殖器HSV-2疾病; 2）确定T细胞受体（TCR）库动力学和 组织驻留记忆CDS T细胞的抗原特异性与生殖器疱疹疾病相关 严重性。我们将从具有不同疾病结局的患者队列中获得连续活检组织：轻度 疾病，定义为复发率< 2 episodes per year and severe disease as recurrence rate >6 每年的事件。该项目将定义成功的外周免疫应答的特征， HSV-2可以在疫苗开发过程中作为免疫的潜在相关物。 相关性（参见说明）： 生殖器疱疹影响17%的美国人口;没有治愈或疫苗可用。我们不知道为什么有些人 感染这种病毒的人病情严重，其他人病情很轻。我们开发了新的实验室 研究生殖器疱疹患者样本中免疫细胞的方法， 研究轻微和严重疾病患者之间的差异，以开发有效的疫苗。