权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10468025
负责人：
Renee M Tsolis
金额：
$ 42.49万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10468025
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

项目摘要

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