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中高度内在的常见寄生虫病。军事人员有这种媒介传播疾病的风险。的确，利什曼病在持久自由的行动（OEF），伊拉克自由（OIF）和新黎明（OND）的行动中达到了美国军方的流行比例。在不同的研究中，无症状与有症状的利什曼病的比例从6：1到98：1。因此，我们的军事人员很有可能与约600人报告的感染更多。利什曼尼亚（Leishmania）即使在临床“治愈”之后，利什曼尼亚（Leishmania）也能够持续存在。实际上，即使疾病症状解决后，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，利什曼尼亚会对感染期间宿主的先天和适应性免疫调查产生深远的影响。最近的证据证明，即使在“治愈”疾病之后，免疫影响仍然存在。这一点，利什曼病的免疫作用很​​有可能超出了可测量的症状疾病。外泌体是从大多数活细胞释放出的小蔬菜，这些蔬菜含有蛋白质，RNA和脂质的原始细胞。现在，外泌体被认为是在宿主细胞之间运输免疫和其他反应信号的主要血管。最近，人们认识到，外泌体这些微小的信息包可能会提供线索，这些线索可以解释利什曼原虫感染的深刻系统作用。我们已经表征了来自利什曼原虫的不同生活阶段的外泌体的蛋白质含量，利什曼原虫是中东利什曼病的真正特工之一。当前的建议基于以下假设：蛋白质和小型RNA在利什曼尼亚外泌体中释放出来或来自利什曼原虫的细胞释放出来，负责利什曼病对免疫细胞反应的戏剧性和持续性局部和全身影响。这些作用可以在活动期间或在渐近感染期间调用。我们的推论认为，利什曼原虫寄生虫本身释放了外部外泌体，其含量会影响细胞内环境，并将其纳入从宿主细胞释放的外泌体中。因此，对释放外泌体的宿主和寄生虫衍生的含量的理解将为利什曼病的诊断和治疗方法提供基础。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，以及从巨噬细胞感染的巨噬细胞释放的途径。假设：来自利什曼原虫感染的巨噬细胞的外泌体包含蛋白质和microRNA，可促进被感染的巨噬细胞的非经典激活。目标＃2。鉴定出在伊拉克获得皮肤利什曼病的美国军方成员的血清中的蛋白质和小RNA，并确定外泌体蛋白是在人类还是感染了L. major或l. m脑杆菌的小鼠中的免疫激素。假设：从利什曼原虫感染的哺乳动物细胞释放的外泌体含有显着的寄生虫抗原，可在受感染的个体中产生免疫响应。目标＃3。记录来自寄生虫的外泌体的免疫调节特性，来自感染的巨噬细胞，或在人类患有利什曼病的血清中循环。免疫反应将在人类巨噬细胞和小鼠和婴儿乳杆菌感染的小鼠模型中进行测试。假设：外泌体暴露的功能性酶促活性，影响激活状态和受感染和旁观者宿主免疫细胞的杀生反应。