课题基金 / 基金详情

Gut Cytotoxic CD4 T cells in HIV-1 Pathogenesis

Gut Cytotoxic CD4 T cells in HIV-1 Pathogenesis
HIV-1 发病机制中的肠道细胞毒性 CD4 T 细胞
批准号:
10318604
负责人:
Mario Luis Santiago
金额:
$44.57万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-07 至 2024-12-31

项目摘要

项目成果

Mario Luis Santiago的其他基金

相似基金

相关文献

中文摘要
翻译
摘要 尽管抗逆转录病毒受到抑制,但HIV-1相关的炎症和慢性免疫激活仍然存在 并与合并症的发展和死亡率的增加密切相关。这个 胃肠道(GI)可能是慢性炎症的主要来源,因为早期HIV-1复制和CD4T 肠道中的细胞枯竭导致粘膜炎症和屏障功能障碍,导致移位 肠道微生物/微生物产物进入固有层和体循环。深入了解 驱动肠道慢性免疫激活的分子过程,我们描绘了肠道的转录组 CD4CD8HIV-T细胞暴露于革兰氏阴性肠杆菌,然后体外感染α-1。多重 颗粒酶基因在微生物暴露后上调,随着HIV-1感染而进一步增强, 提示协同诱导CD4细胞毒性T淋巴细胞(CTL)活性。在试验性的体外研究中, 人类肠道CD4CTL表型与颗粒酶B表达、TCR信号、Th1/17相关 多功能性、对共生菌的反应性和表达GZA、穿孔素和/或CD107a的亚群。这个 来自肠道的CD4T细胞表达的CD4CTL表型比来自外周血的CD4CTL表型要大得多 血液和淋巴组织。重要的是,HIV-1在体外肠道CD4CTL中复制的程度更高。在这里,我们 假设肠道CD4CTL是唯一准备好对肠道微生物做出反应的,这一假设是非常重要的 易受HIV-1介导的杀伤作用,并通过 细胞溶解和促炎机制。深入了解肠道CD4CTL在HIV-1中的作用 发病机制上,我们提出了三个目标。在目标1中,我们将确定微生物菌种和配体是否会诱导肠道 CD4CTL以MHC-II依赖的方式,通过单细胞深入了解肠道CD4CTL的来源和功能 转录切分,并研究这些细胞的稳定性和体外命运。在目标2中,我们将确定如何 HIV-1感染进一步增加肠道CD4T细胞和我们的体外固有层中GZB的产生 聚合培养(LPAC)模型,确定肠道CD4CTL是否加剧直接和旁观者HIV-1介导的 CD4T细胞通过细胞溶解机制死亡。在目标3中,我们将评估GZ分泌的触发因素并解剖 微生物暴露的肠道CD4T细胞体外分泌的GZ的非细胞溶解和促炎特性。 重要的是,我们将探索体内CD4CTL频率和粘膜和 来自特征明确的两组未治疗患者的存档血浆和肠道活检中的系统性炎症 以及治疗慢性HIV-1感染者。总之,这些研究应该提供关键的 关于这一引人注目的肠道免疫细胞亚群的信息及其对粘膜的贡献 炎症和疾病。
英文摘要
ABSTRACT HIV-1-associated inflammation and chronic immune activation persist despite suppressive antiretroviral therapy and are strongly linked to the development of comorbidities and increased mortality. The gastrointestinal (GI) tract is likely a major source of chronic inflammation, as early HIV-1 replication and CD4 T cell depletion in the gut results in mucosal inflammation and barrier dysfunction, leading to the translocation of enteric microbes/microbial products into the lamina propria and the systemic circulation. To gain insights into the molecular processes that drive gut-focused chronic immune activation, we profiled the transcriptome of gut CD4+CD8α- T cells exposed to gram-negative enteric bacteria and then infected with HIV-1 ex vivo. Multiple granzyme genes were upregulated following microbe exposure that was further enhanced with HIV-1 infection, suggesting the synergistic induction of CD4 cytotoxic T lymphocyte (CTL) activity. In pilot ex vivo studies, the human gut CD4 CTL phenotype was associated with granzyme (GZ) B expression, TCR signaling, Th1/17 polyfunctionality, reactivity to commensal bacteria and subsets expressing GZA, perforin and/or CD107a. The CD4 CTL phenotype was expressed in CD4 T cells from the gut to a much greater extent than from peripheral blood and lymphoid tissue. Importantly, HIV-1 replicated to a greater extent in gut CD4 CTLs ex vivo. Here, we hypothesize that gut CD4 CTLs are uniquely primed to respond to enteric microbes, are highly susceptible to HIV-1 mediated killing, and play critical roles in mucosal HIV-1 pathogenesis via cytolytic and pro-inflammatory mechanisms. To gain insights on the role of gut CD4 CTLs in HIV-1 pathogenesis, we propose 3 aims. In Aim 1, we will determine if microbiome species and ligands induce gut CD4 CTLs in an MHC-II-dependent manner, obtain insights into gut CD4 CTL origin and function by single-cell transcriptomics, and investigate the stability and fate of these cells ex vivo. In Aim 2, we will determine how HIV-1 infection further augments GZB production in gut CD4 T cells and using our ex vivo lamina propria aggregate culture (LPAC) model, determine if gut CD4 CTLs exacerbate direct and bystander HIV-1-mediated CD4 T cell death via cytolytic mechanisms. In Aim 3, we will evaluate the triggers for GZ secretion and dissect the non-cytolytic, pro-inflammatory properties of GZs secreted by microbe-exposed gut CD4 T cells ex vivo. Importantly, we will explore the in vivo relationship between CD4 CTL frequencies and markers of mucosal and systemic inflammation in archived plasma and gut biopsies from well-characterized cohorts of both untreated and treated persons with chronic HIV-1 infection. Altogether, these studies should provide critical information on this striking gut immune cell subpopulation and its contribution to mucosal inflammation and disease.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Gut Cytotoxic CD4 T cells in HIV-1 Pathogenesis
  • 批准号:
    9925642
  • 项目类别:
  • 资助金额:
    $44.57万
  • 财政年份:
    2020
  • 负责人:
    Mario Luis Santiago
  • 依托单位:
Gut Cytotoxic CD4 T cells in HIV-1 Pathogenesis
  • 批准号:
    10542815
  • 项目类别:
  • 资助金额:
    $44.57万
  • 财政年份:
    2020
  • 负责人:
    Mario Luis Santiago
  • 依托单位:
Gut Cytotoxic CD4 T cells in HIV-1 Pathogenesis
  • 批准号:
    10082428
  • 项目类别:
  • 资助金额:
    $44.57万
  • 财政年份:
    2020
  • 负责人:
    Mario Luis Santiago
  • 依托单位:
Role of Type I IFNs in Mucosal HIV-1 Immunity and Pathogenesis
  • 批准号:
    9915855
  • 项目类别:
  • 资助金额:
    $54.99万
  • 财政年份:
    2017
  • 负责人:
    Mario Luis Santiago
  • 依托单位:
海外基金