Extracellular vesicles from parasite and host in leishmaniasis

利什曼病是指由利什曼原虫属引起的一系列疾病综合征。 原生动物利什曼病影响居住在流行地区的人，包括最近发生的地点。 美国在中东的军事活动。利什曼病的常见形式包括内脏 利什曼病（VL）是由婴儿利什曼原虫（Leishmania infantum）或L. donovani或皮肤利什曼病（CL）， 通常是由于L。major或L.产于中东和北方非洲的热带地区。的共同特点 不同形式的利什曼病是它们倾向于引起无症状感染，特别是在 健康的主人无症状利什曼病与有症状利什曼病的比例从6.5：1到>100：1不等 在不同的流行地区。由于在培养中回收寄生虫的能力差， 感染的标志物，无症状感染的诊断可能是难以捉摸的。机制和 这些隐性感染的后果在很大程度上是未知的。 识别无症状利什曼病的方法已经改进，导致最近的报告 在2002-2011年期间部署到伊拉克流行地区的士兵中，近20%有证据表明， 持续湖婴儿血液中的感染利什曼病是一种 慢性炎症，我们不知道长期无症状感染的后果 这个原生动物此外，无症状感染的士兵有发展的风险， 如果在以后的几年中发生免疫功能低下，则会出现症状性疾病。 所有的真核细胞都释放细胞外囊泡（EV）到它们的环境中。的子集 已知被称为外泌体的EV传输生物活性蛋白质、微RNA、代谢酶和微RNA。 细胞之间或整个血流中的脂质。我们的初步研究表明， L.在人类细胞和小鼠皮肤中诱导炎症状态， 由传染性寄生虫引起的炎症状态。这一发现使我们假设，至少 在利什曼病期间诱导的一些炎症反应是由释放的外来体引起的 来自完整的寄生虫或来自利什曼病感染的细胞。本申请的目的是： 目的#1：记录不同的细胞释放的EV的蛋白质和miRNA含量的差异。 利什曼原虫种，或幼稚或利什曼原虫暴露的骨髓细胞。 目的#2：询问EV组分在多大程度上负责宿主炎症 在利什曼病的鼠模型中的局部和全身反应。 目的#3：记录健康人血清中循环或尿液中释放的EV之间的差异 人类或患有无症状或有症状的利什曼原虫属的人。感染. 通过这些研究，我们将解决利什曼原虫感染导致释放的假设， EV的内容物诱导许多全身性炎症反应， 利什曼感染.我们希望这些发现将启发设计新的治疗方法， 和/或诊断方法。

Leishmaniasis refers to a constellation of disease syndromes caused by the Leishmania spp. protozoa. Leishmaniasis affects persons residing in endemic regions, including the sites of recent and ongoing US military activities in the Middle East. Common forms of leishmaniasis include visceral leishmaniasis (VL) caused by Leishmania infantum or L. donovani, or cutaneous leishmaniasis (CL), often due to L. major or L. tropica in the Middle East and northern Africa. A common feature of the different forms of leishmaniasis is their propensity to cause asymptomatic infections, particularly in healthy hosts. The ratio of asymptomatic to symptomatic leishmaniasis varies from 6.5:1 in to >100:1 in different endemic regions. Due to the poor ability to recover parasites in culture and imprecise markers for infection, diagnosis of asymptomatic infections can be elusive. The mechanisms and the consequences of these occult infections are largely unknown. Methods to recognize asymptomatic leishmaniasis have improved, leading to a recent report that nearly 20% of soldiers deployed to endemic regions of Iraq during 2002-2011 have evidence of ongoing L. infantum infection in their bloodstream. Leishmaniasis is a disease associated with chronic inflammation, and we do not know the consequences of long-term asymptomatic infection with this protozoan. Furthermore, asymptomatically infected soldiers are at risk for developing symptomatic disease if immunocompromise occurs in later years. All eukaryotic cells release extracellular vesicles (EVs) into their environment. The subset of EVs called exosomes are known to transmit bioactive proteins, microRNAs, metabolic enzymes and lipids between cells or throughout the bloodstream. Our preliminary studies show that exosomes from L. infantum induce an inflammatory state in human cells and in murine skin, which phenocopies the inflammatory state induced by the infectious parasite. This finding led us to hypothesize that at least some of the inflammatory responses induced during leishmaniasis are caused by exosomes released from intact parasites or from leishmania-infected cells. Aims of the current application are: ‘ Aim #1: To document the differences in protein and miRNA content of EVs released by different species of Leishmania, or by naïve or Leishmania-exposed myeloid cells. Aim #2: To query to what extend the components of EVs are responsible for host inflammatory responses in murine models of leishmaniasis, both locally and systemically. Aim #3: To document differences between EVs circulating in serum or released in urine of healthy humans or people with asymptomatic or symptomatic Leishmania spp. infections. Through these studies we will address the hypothesis that Leishmania infection causes the release of EVs whose contents induce many of the systemic inflammatory responses associated with Leishmania spp. infections. We hope that these findings will inspire the design of novel therapeutic and/or diagnostic approaches to leishmaniasis.