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

利什曼病是一种重要的被忽视的热带疾病，在世界范围内发生，由几种具有不同特征的不同寄生虫引起。巴西L.感染与其他形式的利什曼病特别不同，因为疾病的严重程度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方法如果同时增强炎症反应是有害的。我们的新数据强烈表明，巴西乳杆菌的最佳控制需要一种反应，不仅有效地消除寄生虫，而且减少潜在的免疫病理。在一系列的出版物中，我们概述了CD8细胞溶解T细胞通过上调炎性体和诱导IL-1β的释放来驱动炎症的作用。因此，我们的研究以及许多其他小组的研究表明，涉及炎性体和IL-1β产生的免疫病理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治疗方法非常重要。这种疾病的另一个特点是，在巴西东北部，有很高比例的患者无法使用标准药物——锑酸甲氨胺进行治疗。我们最近对巴西螺杆菌患者药物治疗前的利什曼病变进行了大规模转录分析，发现治疗失败与细胞溶解和IL-1β相关基因的表达相关。这些惊人的结果进一步证明了cd8 -炎性体- il -1β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强度。我们最近发现的另一个重要方面是，它们使我们能够根据细胞溶解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目标，以提高我们对炎性小体激活的理解，并开发一种现场测试的方法来预测治疗失败。在目标1中，我们将定义皮肤利什曼病中促进炎性体激活的细胞和信号，使用巴西利什曼病患者和健康受试者的病变和血液中的细胞。在Aim 2中，我们将确定巴西乳杆菌分离株在疾病发展中的作用。并且，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。总的来说，这些研究将提供关于这种疾病的新信息，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。

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.