Malnutrition-related Lymph Node Dysfunction and Risk of Visceral Leishmaniasis

营养不良相关的淋巴结功能障碍和内脏利什曼病的风险

• 批准号: 8702843
• 负责人: Peter C. Melby
• 金额: $ 23.24万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702843
• 关键词: Acute; Adoptive Transfer; Apoptosis; Bone Marrow; CCL2 gene; Cessation of life; Chemotactic Factors; Child; Childhood; Chimera organism; Cues; Cutaneous; Dendritic Cells; Development; Diet; Epidemiology; Failure; Flow Cytometry; Functional disorder; Hematogenous; Host Defense; Human; Impairment; Individual; Infection; Inflammatory; Invaded; Investigation; Iron; Lead; Leishmania; Leishmania donovani; Life; Lymphatic; Malaria; Malnutrition; Microscopy; Modeling; Mus; Myelogenous; Myeloid Cells; Nutrient; Outcome; Parasites; Parasitic Diseases; Phagocytes; Phagocytosis; Population; Predisposition; Production; Proteins; Resources; Risk; Risk Factors; Role; Route; Skin; Time; Visceral Leishmaniasis; Work; Zinc; chemokine; intravital microscopy; killings; latent infection; lymph nodes; macrophage; migration; mortality; multi-photon; neutrophil; public health relevance; research study; response; trafficking; uptake

DESCRIPTION (provided by applicant): The impact of malnutrition in the world is staggering. Malnutrition is thought to directly or indirectly contribute to more than half of all childhood deaths, most of them related to heightened susceptibility to infection. Visceral leishmaniasis (VL), caused by the protozoan Leishmania donovani, is second only to malaria in global mortality among the tropical parasitic diseases. While most people who are infected with Leishmania develop only an asymptomatic latent infection, malnourished individuals have a greatly increased risk for the development of progressive life-threatening VL. Because multiple nutrient deficiencies probably act in concert to impair host defense in human malnutrition, we established a murine model of polynutrient deficiency (PND; deficient in protein, energy, zinc and iron) that closely mimicked moderate acute malnutrition seen in children in resource-poor regions of the world. In this model we recapitulated the epidemiological observations that malnutrition is a risk factor for VL by demonstrating that PND led to a dramatic increase in early dissemination following cutaneous infection with L. donovani. Strikingly, we found that the early visceralization of L. donovani in PND mice was not related to impaired parasite killing, but due to a failure of the skin-draining lymph node (SDLN) to act as a barrier to dissemination. This loss of SDLN barrier function was associated with a significant reduction in the numbers of dendritic cells (DCs) and macrophages, thus leading to an overall reduction in "phagocytic capacity" of the SDLN. The proposed exploratory studies will fill a significant gap in our understanding of the mechanistic underpinnings of malnutrition-related impairment of SDLN function and defense against Leishmania dissemination. In Specific Aim 1 we will determine the mechanism(s) through which malnutrition leads to a reduced number of macrophages and DCs in the SDLN. Using multicolor flow cytometry, adoptive transfer of mixed fluorescent chimeras, and multi-photon microscopy we will determine if malnutrition reduces SDLN myeloid subpopulations by increasing apoptosis and/or decreasing proliferation, and if reduced migration/retention of myeloid cell in the SDLNs explains the malnutrition-related reduction in SDLN phagocytes. In Specific Aim 2 we will determine the impact of malnutrition on the cutaneous response to L. donovani infection. Using strategies similar to those used in Aim 1 we will determine the effect of malnutrition on the recruitment of myeloid cells and uptake of L. donovani following cutaneous infection. We will determine if chemokine expression has a causal role in the reduced number of myeloid cells in the SDLN and clarify the route of trafficking (lymphatic vs. hematogenous) of parasites from the skin in the malnourished host.

描述（由申请人提供）：营养不良在世界上的影响是惊人的。营养不良被认为是直接或间接造成一半以上儿童死亡的原因，其中大多数与感染易感性增加有关。由杜氏利什曼原虫引起的内脏利什曼病（visceralleishmaniasis，VL）是全球仅次于疟疾的热带寄生虫病。虽然大多数感染利什曼原虫的人只发展为无症状的潜伏感染，但营养不良的人发展为进行性危及生命的VL的风险大大增加。由于多种营养素缺乏症可能会在人类营养不良中共同损害宿主防御，因此我们建立了一种多营养素缺乏症（PND;蛋白质、能量、锌和铁缺乏）的小鼠模型，该模型密切模仿世界资源贫乏地区儿童中的中度急性营养不良。在这个模型中，我们通过证明PND导致皮肤感染L后早期传播的急剧增加，概括了流行病学观察结果，即营养不良是VL的危险因素。donovani。我们发现L.在PND小鼠中的donovani与受损的寄生虫杀灭无关，而是由于皮肤引流淋巴结（SDLN）未能充当传播屏障。这一损失 SDLN屏障功能的降低与树突状细胞（DC）和巨噬细胞数量的显著减少相关，从而导致SDLN的“吞噬能力”的总体降低。拟议的探索性研究将填补我们对营养不良相关的SDLN功能损害和防御利什曼原虫传播的机制基础的理解的重大空白。在具体目标1中，我们将确定营养不良导致SDLN中巨噬细胞和DC数量减少的机制。使用流式细胞术，过继转移的混合荧光嵌合体，和多光子显微镜，我们将确定是否营养不良减少SDLN骨髓亚群通过增加凋亡和/或减少增殖，如果减少迁移/保留的骨髓细胞在SDLN解释营养不良相关的减少SDLN吞噬细胞。在具体目标2中，我们将确定营养不良对皮肤对L。Donovani感染使用与目标1中使用的策略相似的策略，我们将确定营养不良对髓样细胞募集和L。皮肤感染后的Donovani。我们将确定趋化因子表达是否在SDLN中髓样细胞数量减少中起因果作用，并阐明营养不良宿主皮肤中寄生虫的运输途径（淋巴与血行）。