Skin microbiome contributions to the pathogenesis of cutaneous leishmaniasis

项目总结 皮肤利什曼病，由感染细胞内寄生虫利什曼病引起，表现为 临床表现的范围从单一的愈合皮损到严重的慢性皮损，包括 包括播散性和粘膜病变，所有这些病变都可能毁容和/或对药物治疗产生抗药性。 病变的解决需要控制寄生虫，调节病理炎症反应，并启动 伤口愈合反应。我们最近发现，利什曼病在小鼠模型和人类中的感染， 导致皮肤微生物群的特定变化，或称生物失调，这些变化有助于 与感染相关的免疫病理反应。在小鼠中，这种变化发生在一种严重程度依赖的 以链球菌属为特征的非愈合性皮肤利什曼病皮损。和解决 以葡萄球菌为特征的病变。利什曼原虫引起的生物失调可传染给非感染者 笼子伴侣，使我们能够表明，先前存在的生物失调会在侮辱后导致更严重的疾病。 在人类中，初步的基因转录研究表明，皮肤利什曼病的损害与 可测量的链球菌读数显示IL-1β表达增加，并对差异表达进行了浓缩 表达与细胞毒性相关的基因。这与我们之前的工作是一致的，在那里我们确定了一条路径 导致由夸大的T细胞毒性引发的严重炎症，导致IL-1β的产生。 这些初步发现为我们描述皮肤的充分性和必要性提供了一个平台 微生物群在皮肤损伤的发展和伤口愈合反应中是必不可少的 病变消退(目标1)。我们的研究表明，营养不良的小鼠表现出免疫反应的变化，并且 我们建议定义与导致损伤的生物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 相关性通过评估患者细菌分离株对小鼠皮损发展和消退的影响， 并通过调查皮肤利什曼病患者的微生物组的预测性质(目标3)。使用 这些研究我们将确定皮肤微生物群如何与免疫反应和伤口相结合 影响疾病结局的治愈反应，这将使我们能够确定要阻止的潜在治疗方法 与生物失调相关的病理，促进伤口愈合，减轻皮肤疾病严重程度 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.