Skin microbiome contributions to the pathogenesis of cutaneous leishmaniasis

皮肤微生物组对皮肤利什曼病发病机制的贡献

• 批准号: 9884728
• 负责人: Elizabeth Anne Grice
• 金额: $ 70.66万
• 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: 2019-03-04 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884728
• 关键词: Address; Antibiotic Therapy; Antiparasitic Agents; Automobile Driving; Bacteria; Brazil; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Cutaneous; Cutaneous Leishmaniasis; Data; Development; Disease; Disease Outcome; Disease Progression; Down-Regulation; Drug resistance; Ensure; Exhibits; Failure; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genus staphylococcus; Human; Immune response; Immunology; Impaired wound healing; Impairment; Infection; Inflammation; Inflammatory Response; Interleukin-1 beta; Leishmania; Leishmaniasis; Lesion; Measurable; Mediating; Mucous Membrane; Mus; Nature; Outcome; Parasite Control; Parasites; Partner in relationship; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient Isolators; Patients; Pharmacotherapy; Play; Production; Regulatory T-Lymphocyte; Resolution; Role; Severities; Severity of illness; Skin; Skin wound healing; Streptococcus; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Treatment outcome; Work; antimicrobial; base; clinically relevant; cytotoxicity; design; differential expression; dysbiosis; effector T cell; healing; immunopathology; improved; microbiome; mouse model; neglected tropical diseases; response; skin microbiome; skin microbiota; wound healing

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.

项目摘要 皮肤利什曼病，通过感染细胞内寄生虫Leishmania带来 临床表现范围，范围从单个愈合病变到严重的慢性病变，包括 散布和粘膜病变，所有这些病变都可能毁容和/或对药物治疗具有抗药性。 病变分辨率需要控制寄生虫，调节病理性炎症反应以及主动性 伤口愈合反应。我们最近发现，利什曼尼亚感染，在鼠模型和人类中， 导致皮肤微生物组或营养不良的特定改变，这些变化有助于 与感染相关的免疫病理反应。在小鼠中，改变发生在严重程度依赖性 方式，具有非愈合的皮肤利什曼病病变，其特征是链球菌属。和解决 以葡萄球菌为特征的病变。利什曼尼亚诱导的营养不良是未感染的 笼子伴侣，使我们能够证明预先存在的营养不良会导致受伤后更严重的疾病。 在人类中，初步基因转录研究表明皮肤利什曼病病变 可测量的链球菌读取暴露于暴露的IL-1β表达增加，并富含差异性 表达与细胞毒性相关的基因。这与我们确定途径的先前工作一致 导致严重的感染是由夸张的T细胞细胞毒性引发的，导致IL-1β产生。 这些初步发现为我们提供了一个平台来描述皮肤的安全性和必要性 微生物组在皮肤病变的发展和伤口愈合反应中，这对于 病变分辨率（目标1）。我们的研究表明，失调小鼠在免疫响应中表现出改变，并且 我们建议定义与营养不良相关的先天和适应性反应，这有助于病变 发育和损害伤口愈合（AIM 2）。重要的是，我们的方法旨在最大化临床 通过评估患者细菌分离株对小鼠病变发育和分辨率的影响，相关性 并通过研究皮肤利什曼病患者中微生物组的预测性质（AIM 3）。和 这些研究我们将确定皮肤微生物组如何与免疫反应和伤口相结合 治愈对影响疾病结果的反应，这将使我们能够识别潜在的疗法来阻止 营养不良相关的病理学，促进伤口愈合的增加，皮肤疾病的严重程度较小 利什曼病患者。