Mechanisms of Parasite Dissemination in Visceral Leishmaniasis

内脏利什曼病寄生虫传播机制

• 批准号: 10302274
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302274
• 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; Persons; 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; 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.

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 影响世界穷人的“被忽视的热带病”。当寄生虫存在时，人们就会被感染 在白蛉媒介的吸血过程中沉积在真皮中。大多数被感染的人 发生潜伏感染，但没有临床疾病。然而，有些人会出现慢性进行性 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。这 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 活动性疾病的发展。 VL 发病机制的理解进展受到以下因素的阻碍： 缺乏适合研究皮肤接种部位寄生虫传播的模型。研究 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。我们的中央 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 将寄生虫从皮肤贩运到内脏器官。我们公布的初步数据表明，三 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。我们 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性 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 矢量传输。我们的工作假设是，皮肤炎症失调，响应 营养不良或白蛉进食，导致骨髓细胞运输和病原体捕获动态发生改变 皮肤。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 炎症单核细胞流入、寄生虫捕获和细胞从皮肤排出。在具体目标 2 中，我们将 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 针注射和媒介传播后的器官。我们的工作假设是增加的骨髓细胞 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 传播。炎症介质和趋化因子及其受体的变化可能是基础 寄生虫贩运到内脏器官。了解寄生虫内脏化背后的机制可以 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。

项目成果

Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.

• DOI: 10.3389/fimmu.2022.846246
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Hematological and Clinical Features Associated with Initial Poor Treatment Outcomes in Visceral Leishmaniasis Patients with and without HIV Coinfection in Gondar, Northwest Ethiopia.

• DOI: 10.3390/tropicalmed8010036
• 发表时间: 2023-01-04
• 期刊: Tropical medicine and infectious disease
• 影响因子: 2.9
• 作者: Ademe M;Osorio Y;Howe R;Atnafu S;Mulaw T;Fikre H;Travi BL;Hailu A;Melby PC;Abebe T
• 通讯作者: Abebe T

Environmental, Metabolic, and Inflammatory Factors Converge in the Pathogenesis of Moderate Acute Malnutrition in Children: An Observational Cohort Study.

• DOI: 10.4269/ajtmh.20-0963
• 发表时间: 2021-03-22
• 期刊: The American journal of tropical medicine and hygiene
• 作者: Patterson GT;Manthi D;Osuna F;Muia A;Olack B;Mbuchi M;Saldarriaga OA;Ouma L;Inziani M;Yu X;Otieno P;Melby PC
• 通讯作者: Melby PC