Host and parasite factors promoting disease and treatment failure in Leishmania braziliensis patients

促进巴西利什曼原虫疾病和治疗失败的宿主和寄生虫因素

• 批准号: 10312781
• 负责人: Lucas P Carvalho
• 金额: $ 15.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-12 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312781
• 关键词: Adopted; Alternative Therapies; Automobile Driving; Biological Markers; Biopsy; Blood; Brazil; CD8B1 gene; Cells; Characteristics; Clinic; Clinical; Cutaneous; Cutaneous Leishmaniasis; Cytolysis; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease Outcome; Disease Progression; Drug resistance; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Transcription; Human; Immune; Immune response; Immunotherapy; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory Response; Interferon Type II; Interleukin-1 beta; Leishmania; Leishmania braziliensis; Leishmaniasis; Lesion; Mediating; Meglumine; Methods; Nitric Oxide; Parasites; Pathologic; Pathology; Pathway interactions; Patient Isolators; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physicians; Population; Production; Protozoa; Public Health; Publications; Publishing; Reproducibility; Research Personnel; Role; Sampling; Series; Severity of illness; Signal Transduction; Testing; Therapeutic; Translating; Treatment Failure; Treatment outcome; Vaccines; alternative treatment; base; biomarker identification; design; drug standard; field study; granulysin; immunopathology; in vivo; inhibitor; insight; mRNA Differential Displays; macrophage; monocyte; neglected tropical diseases; novel; novel therapeutics; patient population; patient screening; point of care; potential biomarker; recruit; response; standard care; standard of care; therapeutic target

Leishmaniasis is an important neglected tropical disease that occurs worldwide and is caused by several different parasites with different characteristics. L. braziliensis infections are particularly distinct from other forms of leishmaniasis, since disease severity is not due to uncontrolled parasite replication, but rather to an exaggerated immune response. Thus, therapeutics designed to increase parasite killing are detrimental if they concomitantly enhance inflammatory responses. Our new data strongly suggests that optimal control of L. braziliensis 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-1β. Thus, our studies, and those of many other groups, indicate that an immunopathologic pathway involving the inflammasome and IL-1β production is a major driver of disease. Understanding the host and parasite factors driving this response will be important for designing new therapies. Another characteristic of this disease is that a high percentage of patients in the Northeast of Brazil fail treatment with the standard drug, meglumine antimoniate. We recently performed a large-scale transcriptional analysis of leishmanial lesions from L. braziliensis patients prior to drug treatment and found that treatment failure correlated with expression of genes associated with cytolysis and IL-1β. These striking results further demonstrate the significance of this CD8-inflammasome-IL-1β pathway in promoting disease, and we hypothesize that drug failure in patients is due to the magnitude of these pathologic responses. Another important aspect of our recent findings is that they allow us to predict, based on the expression of cytolytic genes, which patients will fail the standard treatment. We propose three specific aims to advance our understanding of inflammasome activation and develop a field-tested approach to predicting treatment failure. In Aim 1 we will define the cells and signals contributing to inflammasome activation in cutaneous leishmaniasis, using cells from lesions and blood of L. braziliensis patients and healthy subjects. In Aim 2 we will determine the role of L. braziliensis isolates in disease development. And, in Aim 3 we will assess the ability to predict treatment failure in a clinical setting. Taken together, these studies will provide new information about this disease that can be translated into new therapies, as well as a practical field-testing approach to predicting treatment failure.

利什曼病是一种重要的被忽视的热带疾病，发生在世界各地，由几种具有不同特征的不同寄生虫引起。L.巴西利什曼病感染与其他形式的利什曼病特别不同，因为疾病的严重性不是由于不受控制的寄生虫复制，而是由于过度的免疫反应。因此，设计用于增加寄生虫杀灭的治疗剂如果同时增强炎症反应则是有害的。我们的新数据有力地表明，L。巴西寄生虫需要一种不仅能有效消除寄生虫，而且能降低免疫病理学可能性的反应。在一系列出版物中，我们已经概述了CD8溶细胞性T细胞通过上调炎性小体和诱导IL-1 β释放来驱动炎症的作用。因此，我们的研究和许多其他小组的研究表明，涉及炎性小体和IL-1 β产生的免疫病理学途径是疾病的主要驱动因素。了解驱动这种反应的宿主和寄生虫因素对于设计新的疗法将是重要的。这种疾病的另一个特点是，在巴西东北部，高比例的患者用标准药物锑酸葡甲胺治疗失败。我们最近进行了一个大规模的转录分析利什曼原虫病变从L。结果发现，治疗失败与细胞溶解和IL-1 β相关基因的表达相关。这些惊人的结果进一步证明了这种CD8-炎性体-IL-1 β通路在促进疾病中的重要性，我们假设患者的药物失败是由于这些病理反应的程度。我们最近发现的另一个重要方面是，它们使我们能够根据溶细胞基因的表达来预测哪些患者将无法接受标准治疗。我们提出了三个具体的目标，以提高我们对炎性小体激活的理解，并开发一种经过现场测试的方法来预测治疗失败。在目的1中，我们将使用来自皮肤利什曼病皮损和血液的细胞来确定导致炎性小体激活的细胞和信号。巴西患者和健康受试者。在目标2中，我们将确定L的作用。巴西分离物在疾病发展中的作用。在目标3中，我们将评估在临床环境中预测治疗失败的能力。总之，这些研究将提供有关这种疾病的新信息，这些信息可以转化为新的治疗方法，以及预测治疗失败的实用现场测试方法。