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：
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
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

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

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被忽视的热带疾病，与临床表现有关从相对良性病变到慢性高度溃疡病变到转移性疾病的严重程度。最佳地，药物治疗将消除寄生虫，但迄今为止开发的药物无法诱导无菌性治愈，通常在控制该疾病方面效率低下。我们的新数据强烈表明对皮肤利什曼病的最佳控制需要反应，不仅有效地消除了寄生虫，但也降低了免疫病理学的潜力。在一系列出版物中，我们概述了 CD8细胞溶液T细胞在炎症中驱动炎症中的作用，并诱导释放IL-1。这是我们的研究表明，免疫病理学途径涉及炎症体 IL-1产生是疾病的主要驱动力。我们进一步发现阻止NLRP3或IL-1 严重皮肤利什曼病的实验模型可以改善由没有CTL介导的病理学阻止受保护的免疫反应，这表明这是宿主定向的绝佳目标可以与常规抗寄生虫治疗一起使用的免疫疗法。然而，我们对这种病理反应的了解的显着差距仍然存在。在这里，我们将利用IN的组合体外和体内方法将鉴定经历炎症体激活的细胞，确定激活NLRP3的近端信号，并定义维持这种慢性的趋化因子免疫病理学反应。为了在AIM 1中实现这一目标，我们将确定哪些单元对NLRP3有助于皮肤利什曼病疾病进展过程中的依赖病理通过定义感染后激活炎症，鉴定涉及的细胞并确定哪些细胞促进疾病的炎性体激活需要。在AIM 2中，我们将确定NLRP3的触发器皮肤利什曼病中的炎性体激活。最后，我们发现趋化因子CCL3和 CCL4与患者的治疗失败有关，因此在AIM 3中，我们将确定这些是否是否趋化因子通过促进CD8 T细胞或调节性T驱动皮肤利什曼原虫病变的慢性病细胞募集到利什曼病变。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必需细胞和信号。这样的信息将允许更具体的定位利什曼病的免疫病理学，并确定宿主指导疗法的其他靶标慢性感染。最后，这些研究将具有更一般的意义，因为这种病理途径是皮肤利什曼病并非独有。