Mechanisms of Parasite Dissemination in Visceral Leishmaniasis

内脏利什曼病寄生虫传播机制

基本信息

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
项目类别：
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

项目摘要

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.

内脏利什曼病 (VL) 由细胞内原生动物杜氏利什曼原虫或婴儿利什曼原虫引起，是以下疾病之一影响世界贫困的“被忽视的热带病”当寄生虫感染时，人们就会受到感染。沙蝇媒介的血粉沉积在真皮中，大多数人被感染。出现潜伏感染但没有临床疾病，但有些人会出现慢性进行性感染。感染的特征是发烧、恶病质、巨脾肿大、全血细胞减少并最终死亡。寄生虫从皮肤传播的机制以及只有少数感染者的原因发展为全面性疾病的原因尚不清楚，但营养不良已被确定为该疾病的主要危险因素 VL 发病机制的进展受到了阻碍。缺乏适合研究皮肤接种部位寄生虫传播的模型。这里提出将使用临床相关的动物宿主（营养不良的小鼠）和自然寄生虫传播通过受感染白蛉的叮咬来确定导致 VL 的寄生虫传播机制。假设是寄生虫传播是由改变的皮肤炎症和骨髓细胞介导的我们已发表的初步数据表明，寄生虫从皮肤贩运到内脏器官的过程分为三个阶段。寄生虫传播的组成模型涉及（1）炎症细胞流入部位的增加寄生虫进入皮肤；（2）受感染的骨髓细胞（主要是单核细胞和中性粒细胞）过度迁移 (3) 迁移的受感染骨髓细胞从引流淋巴结逃逸的情况增加。提出营养不良和媒介相关炎症同时存在，就像在流行地区发生的那样世界，将协同促进寄生虫传播和活跃 VL 在具体目标 1 中，我们将确定针注射感染后早期骨髓细胞募集和皮肤中寄生虫命运的动态我们的工作假设是皮肤炎症失调，以应对营养不良或白蛉进食，驱动骨髓细胞运输和病原体捕获的动态特别是，我们将确定失调的炎症如何导致中性粒细胞的差异。在具体目标 2 中，我们将讨论炎症性单核细胞流入、寄生虫捕获和细胞从皮肤中排出。确定骨髓细胞运输和杜氏乳杆菌从皮肤到内脏传播的机制针注射和载体传播后的器官我们的工作假设是骨髓细胞增加。通过传入淋巴管的运输，加上引流淋巴结中细胞滞留的减少，导致寄生虫炎症介质和趋化因子及其受体的变化可能是传播的基础。了解寄生虫内脏化背后的机制可以帮助了解寄生虫向内脏器官的贩运。采取干预措施，降低寄生虫传播和这种毁灭性疾病发展的风险。