Mechanisms of Parasite Dissemination in Visceral Leishmaniasis

内脏利什曼病寄生虫传播机制

• 批准号: 10062846
• 负责人: Peter C. Melby
• 金额: $ 54.82万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062846
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Animals; Bite; Cachexia; Cause of Death; Cells; Cessation of life; Chimera organism; Chronic; Clinical; Color; Confocal Microscopy; Coupled; Cues; Cutaneous; Data; Deposition; Dermis; Development; Dinoprostone; Disease; Epidemiology; Event; Fever; Flow Cytometry; Goals; Hepatosplenomegaly; Human; Impairment; Individual; Infection; Infectious Skin Diseases; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injections; Interleukin-1 beta; Intervention; Investigation; Knockout Mice; Lead; Leishmania; Leishmania donovani; Leukocyte Trafficking; Leukocytes; Ligands; Lymphatic; Malaria; Malnutrition; Mediating; Minority; Modeling; Molecular; Mouse Strains; Mus; Myeloid Cells; Needles; Organ; Pancytopenia; Parasites; Parasitic infection; Pathogenesis; Pharmacology; Process; Production; Publishing; Research; Risk; Risk Factors; Role; Route; Sand Flies; Site; Skin; Splenomegaly; Symptoms; Transgenic Mice; Transgenic Organisms; Visceral; Visceral Leishmaniasis; Work; chemokine; clinically relevant; draining lymph node; feeding; inflammatory milieu; inhibitor/antagonist; latent infection; lymph nodes; migration; monocyte; mouse model; neglected tropical diseases; neutrophil; novel; novel strategies; pathogen; receptor; recruit; response; trafficking; transmission process; vector; vector transmission

Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani or L. infantum, is one of the “Neglected Tropical Diseases” that impacts the poor of the world. People are infected when the parasite is deposited in the dermis during the bloodmeal of the sand fly vector. The majority of people who are infected develop a latent infection without clinical disease. However, some individuals develop a chronic progressive infection characterized by fever, cachexia, massive splenomegaly, pancytopenia and ultimately death. The mechanism of parasite dissemination from the skin and the reason that only a minority of infected individuals develop full-blown disease are not understood, but malnutrition has been identified as a major risk factor for the development of active disease. Progress in understanding the pathogenesis of VL has been hindered by the lack of models suitable for study of parasite dissemination from the site of skin inoculation. The research proposed here will use a clinically relevant animal host (malnourished mice) and natural parasite transmission by the bite of an infected sand fly to define the mechanisms of parasite dissemination that lead to VL. Our central hypothesis is that parasite dissemination is driven by altered cutaneous inflammation and myeloid cell-mediated trafficking of the parasite from the skin to visceral organs. Our published and preliminary data suggest a three- component model of parasite dissemination that involves (1) increased influx of inflammatory cells to the site of parasite entry in the skin; (2) hyper-migration of infected myeloid cells (primarily monocytes and neutrophils) from the skin, and (3) increased escape of migrating infected myeloid cells from the draining lymph node. We propose that co-existent malnutrition- and vector-related inflammation, as would occur in endemic regions of the world, will synergistically promote parasite dissemination and active VL. In Specific Aim 1 we will determine the dynamics of early myeloid cell recruitment and parasite fate in the skin following infection by needle injection and vector-transmission. Our working hypothesis is that dysregulated cutaneous inflammation, in response to malnutrition or sand fly feeding, drives the altered dynamics of myeloid cell trafficking and pathogen capture in the skin. In particular, we will determine how the dysregulated inflammation leads to differences in neutrophil and inflammatory monocyte influx, parasite capture, and cell egress from the skin. In Specific Aim 2 we will determine the mechanisms of myeloid cell trafficking and L. donovani dissemination from the skin to visceral organs following needle injection and vector-transmission. Our working hypothesis is that increased myeloid cell trafficking through the afferent lymphatic, coupled with reduced cell retention in the draining LN, leads to parasite dissemination. Changes in inflammatory mediators and chemokines and their receptors are likely to underpin parasite trafficking to the visceral organs. Understanding the mechanisms behind parasite visceralization can lead to interventions to reduce the risk for parasite dissemination and development of this devastating disease.

由细胞内原生动物Leishmania Donovani或Intantum引起的内脏利什曼病（VL）是一种 影响世界穷人的“被忽视的热带疾病”。当寄生虫是 在沙蝇载体的血液中沉积在真皮中。大多数被感染的人 发展潜在感染而没有临床疾病。但是，有些人发展了一个慢性进步 感染为特征，以发烧，恶病质，大量的脾肿大，全细胞减少症和最终死亡为特征。 寄生虫从皮肤传播的机制和仅感染的个体的原因 不了解成熟疾病，但营养不良已被确定为主要危险因素 活跃疾病的发展。理解VL的发病机理的进展受到了 缺乏适合于从皮肤接种部位研究寄生虫传播的模型。研究 这里提出的将使用临床相关的动物宿主（营养不良的小鼠）和天然寄生虫传播 通过被感染的沙蝇的咬合来定义导致VL的寄生虫传播机制。我们的中心 假设是寄生虫传播是由皮肤注射改变和髓样细胞介导的 从皮肤到内脏器官贩运寄生虫。我们发表的初步数据表明一个三个 寄生虫传播的成分模型，涉及（1）炎症细胞对炎症细胞对该部位的影响增加 皮肤中的寄生虫进入； （2）感染的髓样细胞的过度迁移（主要是单核细胞和中性粒细胞） 从皮肤和（3）增加迁移感染的髓样细胞从排水淋巴结的逃逸。我们 提议与在流行区域的流行区域相连的营养不良和载体相关炎症 世界，将协同促进寄生虫传播和主动VL。在特定目标1中，我们将确定 注射针头感染和 向量传输。我们的工作假设是，对皮肤注射失调，以应对 营养不良或沙蝇喂养，驱动髓样细胞运输和病原体捕获的动力学改变 皮肤。特别是，我们将确定注射失调如何导致中性粒细胞的差异 以及炎症性单核细胞的影响，寄生虫捕获和细胞出口。在特定目标2中，我们将 确定髓样细胞运输和多诺瓦尼乳杆菌从皮肤传播到内脏的机制 针喷射和矢量传输后的器官。我们的工作假设是增加髓样细胞 通过传入淋巴的贩运，再加上降低的排水LN细胞保留，导致寄生虫 传播。炎症介质和趋化因子及其接收器的变化可能会支持 寄生虫贩运到内脏器官。了解寄生虫内脏背后的机制可以 导致干预措施减少寄生虫传播和这种毁灭性疾病的发展的风险。