NRAMP1 IN MACROPHAGE DEFENCES AGAINST INFECTIONS

描述(改编自申请者摘要)：传染病 在北美重新成为一个主要的健康问题，部分原因是 抗生素耐药性普遍出现。防御机制 对抗细胞内寄生虫，以及潜在的细菌策略 宿主吞噬细胞的存活和复制仍然知之甚少。更好的 了解宿主对这种感染的防御可能会提出新的 针对这些疾病的干预策略。使用遗传方法， 研究人员发现了一种新的抗微生物成分(Nramp1) 吞噬细胞的防御。小鼠Nramp1基因突变导致易感性 人类NRAMP1的几种细胞内感染和多态变异是 也与地方性疾病中分枝杆菌感染的易感性有关 疾病的区域。Nramp1是膜转运蛋白大家族中的一员 这从细菌到人类都是高度保守的。Nramp1在 巨噬细胞的溶酶体室，并靶向于 吞噬后不久的细菌吞噬小体。通过与已知知识的同源性 其他Nramp家族成员的底物，他们提出Nramp1的功能是 一种抑制细菌吞噬体膜上的二价阳离子外排泵 复制。目前的提议有四个主要目标。第一，是 了解Nramp1传递如何影响细胞的生理特性 吞噬小体的成熟、酸化和杀菌活性 巨噬细胞和中性粒细胞。第二，是识别底物和 Nramp1在吞噬体膜上的转运机制。三是 确定Nramp1靶向溶酶体的蛋白质决定因素 以及底物结合和运输所必需的残基。第四个是 以独立于Nramp1的方式映射影响宿主的新鼠标位置 对临床相关分支杆菌感染的抵抗力。加在一起，这些 研究应阐明Nramp1在吞噬细胞中的作用和作用机制 抗微生物防御，这反过来又可能提出新的干预途径 在传染病方面。

DESCRIPTION (Adapted from the Applicant's Abstract): Infectious diseases have re-emerged as a major health problem in North America, in part due to the widespread emergence of antibiotics resistance. The mechanisms of defense against intracellular parasites, and the bacterial strategies underlying survival and replication in host phagocytes remain poorly understood. A better understanding of host defenses against such infections may suggest new strategies for intervention in these diseases. Using a genetic approach, the investigators have identified a new component (Nramp1) of anti-microbial defenses of phagocytes. Mutations at Nramp1 in mice cause susceptibility to several intracellular infections, and polymorphic variants at human NRAMP1 are also associated with susceptibility to Mycobacterial infections in endemic areas of disease. Nramp1 is part of a large family of membrane transporters that has been highly conserved from bacteria to man. Nramp1 is expressed in the lysosomal compartment of macrophages and is targeted to the membrane of bacterial phagosomes soon after phagocytosis. By homology with the known substrates of other Nramp family members, they propose that Nramp1 functions as a divalent cation efflux pump at the phagosomal membrane to suppress bacterial replication. The current proposal has four major goals. The first, is to understand how Nramp1 delivery affects the physiological properties of the phagosome including maturation, acidification, and bactericidal activity of macrophages and neutrophils. The second, is to identify the substrate and mechanism of transport of Nramp1 at the phagosomal membrane. The third is to identify protein determinants responsible for Nramp1 targeting to the lysosome and residues essential for substrate binding and transport. The fourth is to map new mouse loci that affect, in an Nramp1-independent fashion, host resistance to infection with clinically relevant Mycobacteria. Together, these studies should clarify the role and mechanism of action of Nramp1 in phagocytes anti-microbial defenses, which may in turn suggest new avenues for intervention in infectious diseases.