Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection

SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用

• 批准号: 10683118
• 负责人: Renee M Tsolis
• 金额: $ 41.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683118
• 关键词: Amino Acids; Anti-Bacterial Agents; Autoimmune; Autoimmune Diseases; Bacteremia; Bacteria; Bacterial Infections; Biology; Brucella abortus; C57BL/6 Mouse; Carrier Proteins; Cattle; Cells; Code; Congenic Mice; Cytosol; Data; Disease; Divalent Cations; Fetal Viability; Generations; Genes; Genetic; Genetic Determinism; Goals; Host Defense; Human; Immune; Impairment; In Vitro; Inbred BALB C Mice; Inbred Mouse; Inbred Strains Mice; Infection; Infection Control; Inflammation; Inflammatory; Leishmania; Link; Macrophage; Mediating; Membrane; Metals; Missense Mutation; Mitochondria; Modeling; Mus; Names; Natural Immunity; Pathology; Phagocytes; Phagosomes; Phenotype; Play; Predisposition; Protein Family; Proteins; Pump; Reactive Oxygen Species; Resistance; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Testing; Vacuole; Vitamin A Deficiency; Work; abortion; antimicrobial; antiporter; bactericide; cell type; expectation; innovation; member; mutant; natural resistance-associated macrophage protein 1; neutrophil; non-tuberculosis mycobacteria; novel; pathogen; pathogenic bacteria; placental infection; solute; tool

ABSTRACT This application proposes to interrogate how the divalent cation transporter NRAMP1/SLC11A1 mediates control of infection with bacterial pathogens. While the function of this transporter has been studied in macrophages, our studies on the link between vitamin A deficiency and susceptibility to Salmonella bacteremia uncovered an unsuspected role for NRAMP1/SLC11A1 in control of systemic S. Typhimurium infection by neutrophils. This finding goes against the conventional wisdom that SLC11A1-dependent host defenses are associated exclusively with macrophages. If true, this would be a novel concept and would represent a major advance in understanding both the role of SLC11A1 and neutrophil function. The long-term goal of this proposed work is to uncover novel mechanisms by which phagocytes control disseminated infections. We propose that a functional difference in neutrophils expressing mutant SLC11A1, as a result of impaired bactericidal mechanisms, increases susceptibility of SLC11A1-deficient mice to pathogens. Our central hypothesis is that SLC11A1 function promotes the bactericidal activity of neutrophils. We will test our hypothesis using the complementary approaches outlined in the following specific aims: (1) Define cell neutrophil-specific functions of SLC11A1 in controlling systemic salmonellosis. (2) Determine the mechanistic basis for SLC11A1 function in neutrophil antimicrobial activity. (3) Define how SLC11A1 promotes neutrophil-mediated disease pathology. Our proposed work is novel and innovative in that the function of SLC11A1 in cell types other than macrophages is not yet known. We will test our hypotheses on the role of SLC11A1 in neutrophils in a rigorous manner and with multiple complementary lines of experimentation. This work is significant in that understanding the role of SLC11A1 in the neutrophil will shed light on how neutrophils control disseminated Salmonella infection, and the results are likely to open the door to studies the role of neutrophils in controlling other pathogens, such as Leishmania and non-tuberculous mycobacteria, in which SLC11A1 function is important. It is our expectation that the results of this work will advance our fundamental understanding of neutrophil biology as well as providing tools and concepts to study the links between SLC11A1 and other infectious and autoimmune pathologies in which this transporter has been implicated.

抽象的 该应用建议询问二价阳离子转运蛋白NRAMP1/SLC11A1如何介导 控制细菌病原体感染。虽然该运输蛋白的功能已在 巨噬细胞，我们对维生素A缺乏症与沙门氏菌易感性之间联系的研究 通过 中性粒细胞。这一发现与传统的观点违反了SLC11A1依赖宿主防御的常规观点 与巨噬细胞专门相关。如果是真的，这将是一个新颖的概念，将代表一个主要的概念 在了解SLC11A1和中性粒细胞功能的作用方面发展。这项提议的长期目标 工作是揭示吞噬细胞控制传播感染的新机制。我们建议 由于杀菌性受损而导致表达突变体SLC11A1的中性粒细胞的功能差异 机制，增加了SLC11A1缺乏病原体的敏感性。我们的中心假设是 SLC11A1功能促进中性粒细胞的杀菌活性。我们将使用 在以下特定目的中概述的互补方法：（1）定义细胞中性粒细胞特异性功能 SLC11A1在控制系统性沙门氏菌中。 （2）确定SLC11A1功能的机械基础 中性粒细胞抗菌活性。 （3）定义SLC11A1如何促进中性粒细胞介导的疾病病理学。我们的 拟议的工作是新颖和创新的，因为Slc11a1在巨噬细胞以外的其他细胞类型中的功能是 尚不清楚。我们将以严格的方式和与 多个互补的实验线。这项工作在理解的作用方面很重要 中性粒细胞中的SLC11A1将阐明中性粒细胞如何控制散布的沙门氏菌感染，并阐明 结果可能会打开研究中性粒细胞在控制其他病原体中的作用的大门，例如 Leishmania和非结核分枝杆菌，其中SLC11A1功能很重要。这是我们的期望 这项工作的结果将提高我们对中性粒细胞生物学的基本理解，并提供 研究SLC11A1与其他感染性和自身免疫性病理之间的联系的工具和概念 该转运蛋白已与之牵涉。