Skin microbiome contributions to the pathogenesis of cutaneous leishmaniasis

项目摘要 皮肤利什曼病是由细胞内寄生虫利什曼原虫感染引起的， 一系列临床表现，从单一愈合病变到严重慢性病变，包括 播散性和粘膜病变，所有这些病变都可能使人毁容和/或对药物治疗有抗性。 病变消退需要寄生虫控制、病理性炎症反应的调节和炎症反应的启动。 伤口愈合反应。我们最近发现利什曼原虫感染，在小鼠模型和人类中， 导致皮肤微生物组的特定改变或生态失调，这些变化有助于 与感染相关的免疫病理反应。在小鼠中，这些变化发生在严重程度依赖的 的方式，与不愈合的皮肤利什曼病病变的特点是链球菌属。和解决 以葡萄球菌属为特征的病变利什曼原虫引起的生态失调可传染给未感染的 笼友，使我们能够表明，预先存在的生态失调导致更严重的疾病后，侮辱。 在人类中，初步的基因转录研究表明，皮肤利什曼病病变， 可测量的链球菌读数显示出增加的IL-1β表达，并富集了差异表达。 表达与细胞毒性相关的基因。这与之前的工作一致，我们发现了一种途径， 导致由过度的T细胞细胞毒性引发的严重炎症，导致IL-1β产生。 这些初步的发现为我们提供了一个平台，以划定皮肤的充分性和必要性 微生物组在皮肤病变的发展和伤口愈合反应中的作用， 病变消退（目标1）。我们的研究表明，生态失调的小鼠表现出免疫反应的变化，并且 我们建议定义与微生态失调相关的先天和适应性反应， 发展和损害伤口愈合（目标2）。重要的是，我们的方法旨在最大限度地提高临床 相关性通过评价患者细菌分离物对小鼠中病变发展和消退的影响， 并通过研究皮肤利什曼病患者中微生物组的预测性质（目的3）。与 这些研究将确定皮肤微生物组如何与免疫反应和伤口整合， 治疗反应，以影响疾病的结果，这将使我们能够确定潜在的治疗，以阻止 在皮肤病中，促进伤口愈合，并减轻疾病严重程度， 利什曼病患者。

PROJECT SUMMARY Cutaneous leishmaniasis, brought about by infection with the intracellular parasite leishmania, exhibits a spectrum of clinical manifestations, ranging from single healing lesions to severe chronic lesions, and including both disseminated and mucosal lesions, all of which can be disfiguring and/or resistant to drug treatment. Lesion resolution requires parasite control, modulation of pathologic inflammatory responses, and initiation of wound healing responses. We recently discovered that leishmania infection, in murine models and in humans, results in specific alterations to the skin microbiome, or dysbiosis, and that these changes contribute to the immunopathologic response associated with infection. In mice, the alterations occurred in a severity-dependent manner, with non-healing cutaneous leishmaniasis lesions characterized by Streptococcus spp. and resolving lesions characterized by Staphylococcus spp. Leishmania-induced dysbiosis was transmissible to non-infected cage-mates, allowing us to show that pre-existing dysbiosis results in more severe disease following an insult. In humans, preliminary gene transcriptional studies show that cutaneous leishmaniasis lesions with measurable Streptococcus reads exhibited increased IL-1β expression and were enriched for differentially expressed genes associated with cytotoxicity. This is in line with previous work where we identified a pathway leading to severe inflammation that is initiated by exaggerated T cell cytotoxicity, leading to IL-1β production. These preliminary findings provide a platform for us to delineate the sufficiency and necessity of the skin microbiome in the development of cutaneous lesions and in the wound healing response that is essential for lesion resolution (Aim 1). Our studies indicate that dysbiotic mice exhibit changes in the immune response, and we propose to define the innate and adaptive responses associated with dysbiosis that contribute to lesion development and impair wound healing (Aim 2). Importantly, our approach is designed to maximize clinical relevance by evaluating the effect of patient bacterial isolates on lesion development and resolution in mice, and by investigating the predictive nature of the microbiome in cutaneous leishmaniasis patients (Aim 3). With these studies we will determine how the skin microbiome integrates with the immune response and the wound healing response to influence disease outcomes, which will allow us to identify potential therapies to block dysbiosis-associated pathology, promote increased wound healing, and lessen disease severity in cutaneous leishmaniasis patients.