Extracellular vesicles from parasite and host in leishmaniasis

利什曼病是指由利什曼原虫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 以及美国在中东正在进行的军事活动。常见的利什曼病包括内脏利什曼病 由婴儿利什曼原虫或杜氏利什曼原虫引起的利什曼病(VL)，或皮肤利什曼病(CL)， 通常是由于中东和北非的大斑潜蝇或热带斑潜蝇引起的。的一个共同特点是 不同形式的利什曼病是它们引起无症状感染的倾向，特别是在 健康的主人。无症状和有症状的利什曼病的比例从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较差，且不准确 感染的标志物，无症状感染的诊断可能难以捉摸。这些机制和 这些隐蔽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有所改进，导致了最近的一份报告 2002-2011年间被部署到伊拉克疫区的近20%的士兵有证据表明 在它们的血液中持续感染婴儿乳杆菌。利什曼病是一种与 慢性炎症，我们不知道长期无症状感染的后果 这种原生动物。此外，无症状感染的士兵有发展的风险。 如果晚年免疫功能受损，就会出现症状性疾病。 所有真核细胞都会将胞外囊泡(EV)释放到环境中。的子集 已知的EV称为外切体，可传递生物活性蛋白、microRNAs、代谢酶和 细胞间或整个血液中的脂类。我们的初步研究表明，来自 婴儿乳杆菌在人类细胞和小鼠皮肤中诱导炎症状态，这一表型复制了 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 利什曼病期间引起的一些炎症反应是由释放的外切体引起的。 来自完整的寄生虫或来自利什曼病感染的细胞。当前应用程序的目标是：‘ 目的#1：记录不同类型电动汽车释放的蛋白质和miRNA含量的差异 利什曼原虫的物种，或由幼稚的或暴露在利什曼原虫的髓系细胞。 目的2：询问EVS的成分在多大程度上对宿主炎症负责 利什曼病小鼠模型的局部和全身反应。 目的#3：记录健康人血清中循环和尿液中释放的EVS的差异 人类或无症状或有症状的利什曼原虫的人。感染。 通过这些研究，我们将解决这样的假设，即利什曼原虫感染导致 EV的内容会引发许多与以下各项相关的全身炎症反应 利什曼原虫感染。我们希望这些发现将启发新的治疗方法的设计 和/或利什曼病的诊断方法。

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.