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
• 负责人: PHILLIP SCOTT
• 金额: $ 55.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10329958
• 关键词: Antiparasitic Agents; Automobile Driving; Benign; Binding; Bioinformatics; CCL3 gene; CCL4 gene; CCR5 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL3 gene; CXCL9 gene; CXCR3 gene; Cell Death; Cells; Chronic; Clinical; Cutaneous; Cutaneous Leishmaniasis; Cytolysis; Cytotoxic T-Lymphocytes; Data; Disease; Disease Progression; Equilibrium; Experimental Models; Future; Generations; Genetic Transcription; Immune; Immune response; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Integration Host Factors; Interleukin-1; Knowledge; Leishmania; Leishmaniasis; Lesion; Link; Lymphocyte; Mediating; Metastatic to; Modeling; Molecular; Mus; Outcome; Parasites; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Production; Publications; Regulatory T-Lymphocyte; Reporter; Role; Series; Severities; Signal Transduction; Sterility; Testing; Treatment Failure; cell injury; cell type; chemokine; chronic infection; design; ex vivo imaging; experimental study; imaging approach; immune imaging; immunopathology; improved; in vitro Model; in vivo; insight; mouse model; neglected tropical diseases; perforin; recruit; response

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，与临床表现有关。 严重程度从相对良性病变到慢性高度溃烂病变再到转移性疾病。 最理想的情况是，药物治疗可以消灭寄生虫，但迄今为止开发的药物并不能导致不育。 而且往往在控制疾病方面效率低得可怜。我们的新数据有力地表明 皮肤利什曼病的最佳控制需要一种反应，不仅有效地消除 寄生虫，但也降低了免疫病理的可能性。在一系列出版物中，我们概述了 CD8细胞通过上调炎症小体和诱导T细胞在炎症反应中的作用 释放IL-1。因此，我们的研究表明，涉及炎症小体的免疫病理途径 而IL-1的产生是疾病的主要驱动力。我们进一步发现，阻断NLRP3或IL-1 重症皮肤利什曼病实验模型改善CTL介导的病理改变 阻断保护性免疫反应，这表明这两种基因都是宿主定向的极好靶标 可与常规抗寄生虫治疗结合使用的免疫疗法。然而， 我们对这种病理反应的认识仍然存在很大差距。这里，我们将使用中的组合 体外和体内方法将识别经历炎性小体激活的细胞，确定 激活NLRP3的近端信号，并定义维持这种慢性疾病的趋化因子 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参与了NLRP3 皮肤利什曼病病情进展过程中的依赖病理学 炎症小体在感染后被激活，识别涉及的细胞并确定哪些细胞 是致病炎症小体激活所必需的。在目标2中，我们将确定NLRP3的触发因素 皮肤利什曼病的炎性小体激活。最后，我们发现趋化因子CCL3和CCL3 CCl4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CD8T细胞或调节性T细胞促进皮肤利什曼病皮损的慢性化 利什曼病皮损的细胞募集。我们提出的实验具有明显的翻译意义，因为 它们建立在从利什曼病患者那里获得的大量数据基础上，旨在识别 疾病所需的基本细胞和信号。这样的信息将允许更具体的目标 利什曼病的免疫病理学研究，并确定宿主导向治疗的其他靶点。 慢性感染。最后，这些研究将具有更普遍的意义，因为这一病理途径是 并非皮肤利什曼病所特有。