The Role of Innate Cells in the Pathogenesis of Leishmania Braziliensis Infection

 描述（由申请人提供）：利什曼病是巴西的一个主要公共卫生问题，我们提出的实验将促进我们对这种疾病的理解，具体目标是确定新的治疗方法。该项目涉及宾夕法尼亚大学和巴西巴伊亚联邦大学之间的合作，包括对巴西Corte de佩德拉利什曼病参考中心治疗的患者的研究。L.巴西脑炎与强烈的炎症反应有关，而炎症反应是该病的主要原因，我们已开始确定所涉及的主要病理反应。我们对巴西利什曼原虫感染的皮肤病变和正常皮肤对照进行了全基因组转录谱分析，并确定了2,000多个差异调节基因。这种转录反应的通路水平分析揭示了与皮肤病理学相关的关键生物通路以及特定基因。这使我们能够产生一个可测试的免疫驱动的病变病理学的“metapathway”模型，为人类利什曼病的治疗提供了新的见解。从我们的全基因组转录谱分析中得出的假设的Meta途径表明，利什曼原虫中的溶细胞 病变促进细胞死亡，导致炎性小体激活分子的释放。炎症小体激活促进IL-1b的产生，从而激活驱动病理的促炎效应机制。我们新的初步研究表明，NK细胞在细胞溶解反应中起着重要作用，在目标1中，我们将定义NK细胞在介导疾病进展中的作用。我们的初步数据表明，NK细胞活化受体NKG 2D参与NK细胞诱导的细胞溶解，因此可能是治疗的靶点。在目标2中，我们将评估IL-1b在促进病理学增加中的作用，并确定IL-1b是否也代表免疫治疗的新靶点。除了这些专注于开发免疫治疗新靶点的研究外，我们还将尝试定义患者治疗失败的新生物标志物。因此，在目标3中，我们将定义疾病严重程度的系统性转录特征以及皮肤微生物组相关性。这些将是第一个研究，以提供一个广泛的了解系统和局部转录的变化，结合表征皮肤微生物群在病变部位。总之，这些研究将增加我们对这种疾病的免疫病理学机制的理解，确定预测患者疾病结局的生物标志物，并为提出使用新的抑制剂作为免疫疗法以促进疾病的临床治愈奠定基础。

 DESCRIPTION (provided by applicant): Leishmaniasis is a major public health problem in Brazil, and we propose experiments that will advance our understanding of this disease with the specific goal of identifying new therapeutic approaches. This project involves collaboration between the University of Pennsylvania and the Federal University of Bahia, Brazil, and includes the study of patients that are treated at the Leishmaniasis Reference Center in Corte de Pedra, Brazil. L. braziliensis is associated with a strong inflammatory response that is the major cause of the disease, and we have begun to identify the major pathologic responses involved. We performed genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls and identified over 2,000 differentially regulated genes. Pathway-level analysis of this transcriptional response revealed key biological pathways, as well as specific genes, associated with cutaneous pathology. This has allowed us to generate a testable 'metapathway' model of immune-driven lesion pathology, providing new insights for treatment of human leishmaniasis. The hypothetical meta- pathway derived from our genome wide transcriptional profiling analysis suggests that cytolytic cells within the leishmanial lesion promote cell death, leading to the release of inflammasome activating molecules. Consequent inflammasome activation promotes IL-1b production, thereby activating pro-inflammatory effector mechanisms that drive pathology. Our new preliminary studies indicate that NK cells play a large role in the cytolytic response, and in Aim 1 we will define the role of NK cells in mediating disease progression. Our preliminary data indicate that an NK cell activating receptor, NKG2D, is involved in NK cells induced cytolysis, and thus could be a target for therapy. In Aim 2 we will assess the role of IL-1b in promoting increased pathology and determine if IL-1b also represents a new target for immunotherapy. In addition to these studies, which focus on the development of new targets for immunotherapy, we will also attempt to define new biomarkers of treatment failure in patients. Thus, in Aim 3 we will define systemic transcriptional signatures, as well as cutaneous microbiome correlates, of disease severity. These will be the first studies to provide a broad understanding of systemic and local transcriptional changes, combined with a characterization of the skin microbiota at the lesion site. Taken together these studies will increase our understand of the mechanisms of immunopathology responsible for this disease, identify biomarkers that predict disease outcome in patients, and lay the foundation for proposing the use of new inhibitors as immunotherapy to promote clinical cure of the disease.