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.

项目概要皮肤利什曼病是一种被忽视的主要热带疾病，与临床表现相关严重程度从相对良性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，药物治疗可以消除寄生虫，但迄今为止开发的药物无法诱导不育我们的新数据强烈表明，这种方法无法治愈疾病，但在控制疾病方面往往效率低下。皮肤利什曼病的最佳控制不仅需要有效消除寄生虫，但也降低了免疫病理学的可能性。在一系列出版物中，我们概述了这一点。 CD8 溶细胞 T 细胞通过上调炎症小体并诱导炎症反应来驱动炎症 IL-1 的释放因此，我们的研究表明，涉及炎症的免疫病理学途径。我们进一步发现，阻断 NLRP3 或 IL-1 的产生是疾病的主要驱动因素。严重皮肤利什曼病的实验模型改善了 CTL 介导的病理学，而无需阻断保护性免疫反应，表明这两者都是宿主定向的极好目标免疫疗法可以与传统的抗寄生虫疗法结合使用。我们对这种病理反应的了解仍然存在重大差距，在这里我们将结合使用以下方法。体外和体内方法将识别经历炎性体激活的细胞，确定激活 NLRP3 的近端信号，并定义维持这种慢性的趋化因子为了实现目标 1 中的免疫病理学反应，我们将确定哪些细胞有助于 NLRP3。通过定义何时发生皮肤利什曼病疾病进展期间的依赖性病理学感染后炎症小体被激活，识别涉及的细胞并确定哪些细胞在目标 2 中，我们将确定 NLRP3 的触发因素。最后，我们发现趋化因子 CCL3 和 CCL4 与患者的治疗失败相关，因此在目标 3 中，我们将确定这些是否趋化因子通过促进 CD8 T 细胞或调节性 T 细胞驱动皮肤利什曼病病变的慢性化我们提出的实验具有明确的转化意义。它们以从利什曼病患者获得的大量数据为基础，旨在识别疾病所需的基本细胞和信号这些信息将允许更具体的靶向。利什曼病的免疫病理学研究，并确定该领域针对宿主的治疗的其他靶点最后，这些研究将具有更普遍的意义，因为这种病理途径是并非皮肤利什曼病所独有。