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
基本信息
- 批准号:8696991
- 负责人:
- 金额:$ 24.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AffectAnatomic SitesAnatomyAnimal ModelAntigenic SpecificityAntigensAntiviral AgentsBiopsyBloodBlood VesselsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCell SurvivalCellsCharacteristicsClinicalClinical ResearchCollaborationsConfocal MicroscopyContainmentDermalDermisDiseaseDisease OutcomeExhibitsFrequenciesFundingGenesGenital systemGenomeGoalsGrantHerpesvirus 1HumanHuman Herpesvirus 2Human VolunteersImmuneImmune responseImmunityImmunologic SurveillanceIn SituIndividualInfectionKineticsKnowledgeLaboratoriesLesionLyticMeasuresMemoryMessenger RNAMetabolicMetabolismMethodsMucosal ImmunityMucous MembraneMusOutcomeParticipantPathogenesisPatientsPeripheralPhysiologicalPlayPopulationPositioning AttributePropertyProteinsRecurrenceRoleSamplingSensory Nerve EndingsSeverity of illnessSimplexvirusSiteSkinStudy modelsT-Cell ActivationT-Cell ReceptorT-LymphocyteTechnologyTissuesUlcerVaccine DesignVaccinesVaccinia Virus StudyViralVirionVirusVirus Diseasescell typechemokineclinical epidemiologycohortcomplementarity-determining region 3cytokinedeep sequencingdensitygenital herpeshuman datahuman tissuein vivoinsightlaser capture microdissectionparticlepathogenreactivation from latencyresponsespatiotemporalvaccine development
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Jia Zhu', 18)}}的其他基金
Genetic Dissection of the Pathophysiology of Polycystic Ovary Syndrome
多囊卵巢综合征病理生理学的基因剖析
- 批准号:
10739832 - 财政年份:2023
- 资助金额:
$ 24.41万 - 项目类别:
Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Men and Children
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- 批准号:
10395951 - 财政年份:2021
- 资助金额:
$ 24.41万 - 项目类别:
Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Men and Children
通过定义与男性和儿童 PCOS 遗传风险因素相关的表型来剖析 PCOS 生理学
- 批准号:
10230375 - 财政年份:2021
- 资助金额:
$ 24.41万 - 项目类别:
Modeling of human HSV infection: development of immune-competent 3D skin-on-chip with vascular perfusion
人类 HSV 感染建模:开发具有血管灌注功能的免疫活性 3D 皮肤芯片
- 批准号:
10328978 - 财政年份:2020
- 资助金额:
$ 24.41万 - 项目类别:
Modeling of human HSV infection: development of immune-competent 3D skin-on-chip with vascular perfusion
人类 HSV 感染建模:开发具有血管灌注功能的免疫活性 3D 皮肤芯片
- 批准号:
10555337 - 财政年份:2020
- 资助金额:
$ 24.41万 - 项目类别:
Mechanisms of Protective Local Immunity in Human Female Reproductive Tract
人类女性生殖道保护性局部免疫机制
- 批准号:
9220697 - 财政年份:2014
- 资助金额:
$ 24.41万 - 项目类别:
Mechanisms of Protective Local Immunity in Human Female Reproductive Tract
人类女性生殖道保护性局部免疫机制
- 批准号:
8705241 - 财政年份:2014
- 资助金额:
$ 24.41万 - 项目类别:
Mechanisms of Protective Local Immunity in Human Female Reproductive Tract
人类女性生殖道保护性局部免疫机制
- 批准号:
8816031 - 财政年份:2014
- 资助金额:
$ 24.41万 - 项目类别:
Mechanisms of CD8+ T cell Immune surveillance in human genital skin and mucosa af
CD8 T细胞对人类生殖器皮肤和粘膜免疫监测的机制
- 批准号:
8508374 - 财政年份:2012
- 资助金额:
$ 24.41万 - 项目类别:
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 - 财政年份:
- 资助金额:
$ 24.41万 - 项目类别:
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