CD8 T cell-dependent pathways leading to immunopathology in cutaneous leishmaniasis

CD8 T 细胞依赖性途径导致皮肤利什曼病的免疫病理学

基本信息

  • 批准号:
    10556387
  • 负责人:
  • 金额:
    $ 55.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-12 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Cutaneous leishmaniasis is a major neglected tropical disease that is associated with clinical manifestations ranging in severity from relatively benign lesions to chronic highly ulcerated lesions to metastatic disease. Optimally, drug treatment would eliminate the parasites, but drugs developed to date fail to induce sterile cure and are often woefully inefficient at controlling the disease. Our new data strongly suggests that optimal control of cutaneous leishmaniasis requires a response that not only effectively eliminates the parasite, but also reduces the potential for immunopathology. In a series of publications, we have outlined the role of CD8 cytolytic T cells in driving inflammation by upregulating the inflammasome and inducing the release of IL-1. Thus, our studies indicate that an immunopathologic pathway involving the inflammasome and IL-1 production is a major driver of disease. We further found that blocking NLRP3 or IL-1 in experimental models of severe cutaneous leishmaniasis ameliorates pathology mediated by CTLs without blocking protective immune responses, suggesting that either would be excellent targets for host-directed immunotherapy that could be used in conjunction with conventional anti-parasitic treatments. However, significant gaps in our knowledge of this pathologic response remain. Here we will utilize a combination of in vitro and in vivo approaches that will identify the cells undergoing inflammasome activation, determine the proximal signals that activate NLRP3, and define the chemokines that maintain this chronic immunopathologic response. To accomplish this in Aim 1 we will determine which cells contribute to NLRP3 dependent pathology during cutaneous leishmaniasis disease progression by defining when inflammasomes are activated following infection, identifying the cells involved and determining which cells are required for disease-promoting inflammasome activation. In Aim 2 we will identify the triggers of NLRP3 inflammasome activation in cutaneous leishmaniasis. Finally, we found that the chemokines CCL3 and CCL4 are associated with treatment failure in patients, and therefore in Aim 3 we will determine if these chemokines drive the chronicity of cutaneous leishmania lesions by promoting CD8 T cell or regulatory T cell recruitment to leishmanial lesions. Our proposed experiments have clear translational significance since they are founded upon substantial data obtained from leishmaniasis patients and are designed to identify the essential cells and signals required for disease. Such information will allow for a more specific targeting of immunopathology in leishmaniasis and identify additional targets for host-directed therapies in this chronic infection. Finally, these studies will be of more general significance, as this pathologic pathway is not unique to cutaneous leishmaniasis.
项目摘要 皮肤利什曼病是一种主要的被忽视的热带疾病,是与临床表现 其严重程度从相对良性的病变到慢性高度溃疡性病变再到转移性疾病。 最理想的情况是,药物治疗将消除寄生虫,但迄今为止开发的药物未能诱导不育 治愈,而且往往在控制疾病方面效率低下。我们的新数据有力地表明, 皮肤利什曼病的最佳控制需要不仅有效消除 寄生虫,但也降低了免疫病理学的可能性。在一系列出版物中,我们概述了 CD 8细胞溶解性T细胞通过上调炎性体和诱导炎症反应来驱动炎症的作用。 IL-1 β的释放。因此,我们的研究表明,一个涉及炎性小体的免疫病理学途径, 而IL-1 β的产生是疾病的主要驱动因素。我们进一步发现,阻断NLRP 3或IL-1受体, 严重皮肤利什曼病的实验模型改善了CTL介导的病理学, 阻断保护性免疫反应,这表明两者都是宿主定向免疫的极好靶点。 免疫疗法可与常规抗寄生虫治疗联合使用。然而,在这方面, 我们对这种病理反应的认识仍然存在重大差距。在这里,我们将结合使用 体外和体内方法将鉴定经历炎性小体活化的细胞,确定炎性小体活化的程度。 激活NLRP 3的近端信号,并定义维持这种慢性炎症的趋化因子。 免疫病理反应为了在目标1中实现这一点,我们将确定哪些细胞有助于NLRP 3 皮肤利什曼病进展过程中的依赖性病理学, 炎症小体在感染后被激活,识别所涉及的细胞并确定哪些细胞 是疾病促进炎性小体激活所必需的。在目标2中,我们将确定NLRP 3的触发因素 皮肤利什曼病中的炎性小体活化。最后,我们发现趋化因子CCL 3和 CCL 4与患者的治疗失败有关,因此在目标3中,我们将确定这些 趋化因子通过促进CD 8 T细胞或调节性T细胞活化, 细胞募集到利什曼病病灶。我们提出的实验具有明确的翻译意义,因为 它们建立在从利什曼病患者获得的大量数据上, 疾病所需的基本细胞和信号。这些信息将有助于更具体地确定目标 利什曼病的免疫病理学,并确定其他目标,为主机定向治疗, 慢性感染最后,这些研究将具有更普遍的意义,因为这种病理途径是 不是皮肤利什曼病所特有的

项目成果

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PHILLIP SCOTT其他文献

PHILLIP SCOTT的其他文献

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{{ truncateString('PHILLIP SCOTT', 18)}}的其他基金

2023 Woods Hole Immunoparasitology Meeting
2023 年伍兹霍尔免疫寄生虫学会议
  • 批准号:
    10680864
  • 财政年份:
    2023
  • 资助金额:
    $ 55.78万
  • 项目类别:
2022 WOODS HOLE IMMUNOPARASITOLOGY MEETING
2022 年伍兹霍尔免疫寄生虫学会议
  • 批准号:
    10458244
  • 财政年份:
    2022
  • 资助金额:
    $ 55.78万
  • 项目类别:
CD8 T cell-dependent pathways leading to immunopathology in cutaneous leishmaniasis
CD8 T 细胞依赖性途径导致皮肤利什曼病的免疫病理学
  • 批准号:
    10329958
  • 财政年份:
    2020
  • 资助金额:
    $ 55.78万
  • 项目类别:
23rd Annual Woods Hole Immunoparasitology (WHIP) Meeting
第 23 届伍兹霍尔免疫寄生虫学 (WHIP) 年度会议
  • 批准号:
    9750405
  • 财政年份:
    2019
  • 资助金额:
    $ 55.78万
  • 项目类别:
20th Annual Woods Hole Immunoparasitology Meeting
第 20 届伍兹霍尔免疫寄生虫学年度会议
  • 批准号:
    9126050
  • 财政年份:
    2016
  • 资助金额:
    $ 55.78万
  • 项目类别:
Resident Memory T cells in Leishmaniasis
利什曼病中的常驻记忆 T 细胞
  • 批准号:
    9916704
  • 财政年份:
    2016
  • 资助金额:
    $ 55.78万
  • 项目类别:
Annual Woods Hole Immunoparasitology (WHIP) Meeting
年度伍兹霍尔免疫寄生虫学 (WHIP) 会议
  • 批准号:
    8899229
  • 财政年份:
    2015
  • 资助金额:
    $ 55.78万
  • 项目类别:
Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis
CD8 T 细胞在利什曼病中的保护和病理作用
  • 批准号:
    8758136
  • 财政年份:
    2014
  • 资助金额:
    $ 55.78万
  • 项目类别:
Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis
CD8 T 细胞在利什曼病中的保护和病理作用
  • 批准号:
    8895257
  • 财政年份:
    2014
  • 资助金额:
    $ 55.78万
  • 项目类别:
Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis
CD8 T 细胞在利什曼病中的保护和病理作用
  • 批准号:
    9300849
  • 财政年份:
    2014
  • 资助金额:
    $ 55.78万
  • 项目类别:

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以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
  • 批准号:
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  • 财政年份:
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