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）：营养不良对世界的影响是惊人的。营养不良被认为直接或间接导致了一半以上的儿童死亡，其中大多数与感染的易感性增加有关。内脏利什曼病（VL）由原生动物杜氏利什曼原虫引起，在热带寄生虫病中全球死亡率仅次于疟疾。虽然大多数感染利什曼原虫的人仅出现无症状的潜伏感染，但营养不良的个体出现进行性危及生命的利什曼原虫的风险大大增加。由于多种营养素缺乏可能协同作用，损害人类营养不良中的宿主防御，因此我们建立了多营养素缺乏（PND；缺乏蛋白质、能量、锌和铁）的小鼠模型，该模型密切模仿资源贫乏儿童中出现的中度急性营养不良。世界各地区。在该模型中，我们通过证明 PND 导致杜氏乳杆菌皮肤感染后早期传播急剧增加，重申了流行病学观察结果，即营养不良是 VL 的危险因素。引人注目的是，我们发现PND小鼠中杜氏乳杆菌的早期内脏化与寄生虫杀灭能力受损无关，而是由于皮肤引流淋巴结（SDLN）未能起到传播屏障的作用。这个损失 SDLN 屏障功能的下降与树突状细胞 (DC) 和巨噬细胞数量的显着减少有关，从而导致 SDLN“吞噬能力”的总体下降。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上的重大空白。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。使用多色流式细胞术、混合荧光嵌合体的过继转移和多光子显微镜，我们将确定营养不良是否通过增加细胞凋亡和/或减少增殖来减少 SDLN 骨髓亚群，以及 SDLN 中骨髓细胞迁移/保留的减少是否可以解释营养不良SDLN 吞噬细胞相关减少。在具体目标 2 中，我们将确定营养不良对杜氏乳杆菌感染的皮肤反应的影响。使用与目标 1 中使用的策略类似的策略，我们将确定营养不良对皮肤感染后骨髓细胞的募集和杜氏乳杆菌摄取的影响。我们将确定趋化因子表达是否与 SDLN 中骨髓细胞数量减少有关，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）。