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: 10224776
• 负责人: Renee M Tsolis
• 金额: $ 43.9万
• 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/10224776
• 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; Fibrinogen; 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; Light; Link; Mediating; Membrane; Metals; Missense Mutation; Mitochondria; Modeling; Mus; Natural Immunity; Pathology; Phagocytes; Phenotype; Play; Predisposition; Protein Family; Proteins; Pump; Reactive Oxygen Species; Resistance; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Testing; Vacuole; Vitamin A; Vitamin A Deficiency; Work; abortion; antimicrobial; antiporter; bactericide; cell type; expectation; innovation; macrophage; 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.

摘要 本申请建议询问二价阳离子转运体NRAMP1/SLC11A1如何介导 控制细菌病原体感染。虽然这种转运蛋白的功能已经在 巨噬细胞，我们对维生素A缺乏与沙门氏菌菌血症易感性的研究 发现NRAMP1/SLC11A1在控制系统性鼠伤寒沙门氏菌感染中的未被怀疑的作用 中性粒细胞。这一发现与传统观点相反，即依赖SLC11A1的主机防御 仅与巨噬细胞相关。如果这是真的，这将是一个新的概念，并将代表一个重大的 了解SLC11A1的作用和中性粒细胞功能的进展。这一提议的长期目标是 工作是揭示吞噬细胞控制播散性感染的新机制。我们建议一项 中性粒细胞表达突变型SLC11A1的功能差异，是杀菌作用受损的结果 机制，增加SLC11A1缺陷小鼠对病原体的易感性。我们的中心假设是 SLC11A1功能可促进中性粒细胞的杀菌活性。我们将使用 在下列具体目标中概述的补充方法：(1)确定细胞中性粒细胞的特异性功能 SLC11A1在控制系统性沙门氏菌病中的作用(2)确定SLC11A1功能的机理基础 中性粒细胞的抗菌活性。(3)明确SLC11A1如何促进中性粒细胞介导的疾病病理。我们的 拟议的工作是新颖和创新的，因为SLC11A1在巨噬细胞以外的细胞类型中的功能是 还不知道。我们将以严格的方式测试SLC11A1在中性粒细胞中的作用假说 多条互补的实验路线。这项工作对于理解 中性粒细胞中的SLC11A1将揭示中性粒细胞如何控制播散性沙门氏菌感染，以及 这些结果可能会为研究中性粒细胞在控制其他病原体中的作用打开大门，例如 利什曼原虫和非结核分枝杆菌，其中SLC11A1功能是重要的。这是我们的期望 这项工作的结果将促进我们对中性粒细胞生物学的基本理解，并为 研究SLC11A1与其他感染性和自身免疫性病理之间联系的工具和概念 这个传送者被牵连进来了。