The Role of Exosomes in the Pathogenesis of Leishmaniasis

外泌体在利什曼病发病机制中的作用

• 批准号: 9339484
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339484
• 关键词: Affect; Afghanistan; American; Antigens; Biological Response Modifiers; Cells; Chronic; Clinical; Country; Cutaneous; Cutaneous Leishmaniasis; Diagnosis; Disease; Disease Outbreaks; Distant; Environment; Epidemic; Exhibits; Freedom; HIV Infections; Human; Immune; Immune response; Immunity; Immunocompromised Host; Individual; Infection; Iraq; Kuwait; Lead; Leishmania; Leishmania infantum; Leishmania major; Leishmaniasis; Life; Lipids; Location; Mammalian Cell; Measurable; Methods; MicroRNAs; Microbe; Middle East; Military Personnel; Mus; Nature; Organ; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Persons; Property; Proteins; Protozoa; Publications; RNA; Reporting; Risk; Role; Sampling; Serum; Signal Transduction; Skin Ulcer; Small RNA; Soldier; Symptoms; Testing; Urine; Vector-transmitted infectious disease; Vesicle; Virulence; Visceral; Visceral Leishmaniasis; World War II; adaptive immune response; base; cell type; exosome; human disease; immunoregulation; macrophage; member; microbial; microbicide; monocyte; mouse model; novel strategies; operation; peripheral blood; public health relevance; response; vesicular release

 DESCRIPTION (provided by applicant): Leishmaniasis refers to a group of common parasitic diseases that are highly endemic in many nations including most Middle Eastern countries. Military personnel are at risk for this vector-borne disease. Indeed, leishmaniasis reached epidemic proportions in the US military during the Operations Enduring Freedom (OEF), Iraqi Freedom (OIF) and New Dawn (OND). The ratio of asymptomatic to symptomatic leishmaniasis varies from 6:1 to 98:1 in different studies. It is therefore highly likely that there are many more unrecognized infections in our military personnel than the ~600 reported. Leishmania have the ability to persist in a host even after clinical "cure". Indeed, infected humans and other hosts may never clear the infection, even after disease symptoms resolve. Leishmania are known to exert a profound effect on innate and adaptive immune responses of the host during infection. Recent evidence documents that immune effects persist even after "cure" of disease. Thus, it is highly likely that the immune effects of leishmaniasis extend beyond measurable symptomatic disease. Exosomes are small vesicles released from most living cells that contain protein, RNA and lipids from the cell of origin. Exosomes are now recognized as major vessels transporting immune and other response signals between host cells. Recently it was recognized that exosomes are released from Leishmania parasites. These tiny packages of information may provide clues that explain the profound systemic effects of Leishmania infection. We have already characterized the protein content of exosomes from different life stages of Leishmania infantum, one of the causative agents of leishmaniasis in the Middle East. The current proposal is based on the hypothesis that proteins and small RNAs released in exosomes from Leishmania or from Leishmania-infected cells are responsible for the dramatic and persistent local and systemic effects of leishmaniasis on immune cell responses. These effects could be invoked during active or during asymptomatic infection. Our corollary posits that Leishmania parasites themselves release exosomes whose contents affect the intracellular environment, and which become incorporated themselves into exosomes released from host cells. An understanding of the host- and parasite-derived content of released exosomes, therefore, would provide the basis for novel approaches to diagnosis and therapy of leishmaniasis. Specific aims of this project are: Aim #1. Identify the protein and small RNA content of exosomes, and the pathway of exosome release from macrophages infected with L. major or L. infantum. Hypothesis: Exosomes from leishmania- infected macrophages contain protein and microRNAs that promote non-classical activation of infected macrophages. Aim #2. Identify proteins and small RNAs in the serum and urine exosomes from members of the US military who acquired cutaneous leishmaniasis in Iraq, and determine whether exosome proteins elicit an immune response in humans or in mice infected with L. major or L. infantum. Hypothesis: Exosomes released from Leishmania-infected mammalian cells contain dominant parasite antigens that generate an immune response in the infected individual. Aim #3. Document the immunomodulatory properties of exosomes from parasites, from infected macrophages, or circulating in serum of humans with leishmaniasis. Immune responses will be tested in human macrophages and in mouse models of L. major and L. infantum infection. Hypothesis: Exosomes exhibit functional enzymatic activities that affect the activation state and the microbicidal response of both the infected and bystander host immune cells.

 描述（由申请人提供）： 利什曼病是指在包括大多数中东国家在内的许多国家高度流行的一组常见寄生虫病。事实上，利什曼病在持久自由行动期间在美国军队中达到了流行程度。 OEF)、伊拉克自由 (OIF) 和新黎明 (OND) 在不同的研究中，无症状利什曼病与有症状利什曼病的比例从 6:1 到 98:1 不等。即使在临床“治愈”后，我们的军事人员中未被识别的感染也可能比报告的约 600 例利什曼原虫要多得多。事实上，即使在患病后，受感染的人类和其他宿主也可能永远无法清除感染。众所周知，利什曼原虫在感染过程中对宿主的先天性和适应性免疫反应产生深远的影响，即使在疾病“治愈”后，免疫作用仍然存在。利什曼病超出了可测量的症状疾病范围，外泌体是大多数活细胞释放的小囊泡，含有来自原始细胞的蛋白质、RNA 和脂质。最近，外泌体被认为是在宿主细胞之间传递免疫和其他反应信号的主要血管。外泌体来自利什曼原虫寄生虫，这些微小的信息包可能提供解释利什曼原虫感染的深远系统影响的线索。婴儿利什曼原虫是中东利什曼病的病原体之一，目前的提议基于这样的假设：利什曼原虫或利什曼原虫感染细胞的外泌体中释放的蛋白质和小RNA是导致这种戏剧性和持久性的原因。利什曼病对免疫细胞反应的局部和全身影响可以在活动期或无症状感染期间引起，我们的推论是利什曼原虫本身释放的。因此，了解释放的外泌体的宿主和寄生虫来源的内容将为诊断和治疗利什曼病的新方法提供基础。该项目的具体目标是：目标#1。确定外泌体的蛋白质和小 RNA 含量，以及感染硕大乳杆菌或婴儿乳杆菌的巨噬细胞释放外泌体的途径。受利什曼原虫感染的巨噬细胞含有促进受感染巨噬细胞非经典激活的蛋白质和小 RNA 目标#2 鉴定在伊拉克感染皮肤利什曼病的美国军人的血清和尿液外泌体中的蛋白质和小 RNA，并确定外泌体是否存在。蛋白质在感染硕大利什曼原虫或婴儿利什曼原虫的小鼠中引发免疫反应假设：利什曼原虫感染的哺乳动物细胞释放的外泌体含有显性寄生虫抗原。目标#3：记录来自寄生虫、受感染巨噬细胞或利什曼病患者血清中循环的外泌体的免疫调节特性，并将在人类巨噬细胞和 L 型小鼠模型中进行测试。假设：外泌体表现出功能性酶活性，影响受感染和旁观者宿主免疫细胞的激活状态和杀菌反应。