Extracellular vesicles from parasite and host in leishmaniasis

利什曼病寄生虫和宿主的细胞外囊泡

• 批准号: 10166594
• 负责人: Mary E Wilson
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166594
• 关键词: Address; Affect; Afghanistan; Bite; Blood Banks; Blood Circulation; Brazil; Cells; Central America; Characteristics; Chronic; Clinical; Country; Cutaneous Leishmaniasis; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Environment; Enzymes; Eukaryotic Cell; European; Exposure to; Geographic Locations; Goals; Health; Human; Immune response; Immunocompromised Host; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Iraq; Leishmania; Leishmania donovani; Leishmania infantum; Leishmaniasis; Lipids; Measures; Metabolic; Methods; MicroRNAs; Middle East; Military Personnel; Mus; Myeloid Cells; Northern Africa; Parasites; Pathogenicity; Persons; Phenocopy; Phenotype; Proteins; Protozoa; Reporting; Risk; Sand Flies; Serum; Signal Transduction; Site; Skin; Small RNA; Soldier; Source; South America; Syndrome; Urine; Vesicle; Visceral; Visceral Leishmaniasis; antigen diagnostic; design; exosome; extracellular vesicles; improved; keratinocyte; low and middle-income countries; member; microbicide; microvesicles; military operation; mouse model; novel therapeutics; pathogen; systemic inflammatory response; vector; vesicular release

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.

利什曼病是指利什曼原虫属引起的疾病综合征星座。 原生动物。利什曼病影响居住在地方性地区的人，包括最近的地点 以及中东正在进行的美国军事活动。利什曼病的常见形式包括内脏 利什曼病（VL）是由利什曼原虫或多诺瓦尼（L. donovani）或皮肤利什曼病（CL）引起的， 通常是由于中东和北非的L. major或L. tropica。一个共同特征的 不同形式的利什曼病是他们承诺引起渐近感染，尤其是在 健康的宿主。无症状与有症状的利什曼病的比例从6.5：1到> 100：1 在不同的内在区域。由于恢复培养和侵犯的寄生虫的能力不佳 感染的标记，渐近感染的诊断可能是弹性的。机制和 这些神秘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有所改善，导致了最近的报告 在2002 - 2011年期间，几乎有20％的士兵部署到伊拉克地方性地区 他们的血液中正在进行的婴儿乳杆菌感染。利什曼病是与 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，不对称感染的士兵有发展的风险 有症状的疾病，如果后来发生免疫功能障碍。 所有真核细胞将细胞外蔬菜（EV）释放到其环境中。子集 已知称为外泌体的电动汽车可传递生物活性蛋白，microRNA，代谢酶和 细胞之间或整个血液之间的脂质。我们的初步研究表明，来自 婴儿乳杆菌在人类细胞和鼠皮中诱发炎症状态 传染性寄生虫引起的炎症状态。这一发现使我们至少假设 利什曼病期间引起的一些炎症反应是由释放的外泌体引起的 来自完整的寄生虫或来自利什曼原虫的细胞。当前申请的目的是：‘ 目的1：记录不同的电动汽车蛋白质和miRNA含量的差异 利什曼原虫的种类，或通过幼稚或利什曼尼亚暴露的髓样细胞。 目标＃2：查询扩展电动汽车组成部分的原因是宿主炎症的原因 在本地和系统上，利什曼病的鼠模型中的反应。 目的＃3：记录EVS在血清中循环或健康尿中释放的EV之间的差异 人类或渐近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Leishmania感染导致释放的假设 电动汽车的内容影响许多与之相关的系统性炎症反应 利什曼尼亚属。感染。我们希望这些发现会激发新疗法的设计 和/或利什曼病的诊断方法。