Genetic and molecular basis of host resistance to Yersinia pestis.

描述（由申请人提供）：鼠疫耶尔森氏菌是腺鼠疫、败血症鼠疫和肺鼠疫的病原体，是一种严重的生物恐怖主义威胁。对Y.鼠疫的致病机理一直致力于鉴定和确定许多毒力因子的功能，这些毒力因子使这种生物体能够破坏宿主的防御。相比之下，相对较少的研究直接检查那些免疫反应，可能是有效的宿主防御Y。鼠疫该建议采取了一种无偏见的方法，旨在确定BALB/cJ小鼠对Y.鼠疫，这似乎是由吞噬细胞的早期防御介导的。该建议的第一个目的是通过经典的正向遗传筛选和称为鼠疫抗性基因座1（prl 1）的抗性基因座的精细定位来确定BALB/cJ小鼠抗性的遗传基础。该分析将 再加上来自抗性和敏感菌株的吞噬细胞基因表达数据。第二个目的是研究BALB/cJ巨噬细胞和中性粒细胞在体外增强的吞噬和杀菌活性以及对Y。鼠疫菌的细胞毒性和细胞凋亡。目的2还将比较研究在Y.抗性和敏感小鼠品系的鼠疫感染。将通过将这些先天免疫细胞从耐药prl 1品系过继转移至易感小鼠，评估中性粒细胞在BALB/cJ耐药中的关键作用。这些研究结果不仅有助于更好地理解宿主对Y染色体的防御。鼠疫在啮齿动物种群，构成了这种病原体的主要环境水库，但可能普遍适用于了解人类对这种病原体的免疫。宿主防御系统是抵抗Y.鼠疫很可能是新的，可以确定感染后治疗干预的早期先天免疫靶点。 公共卫生相关性：作为鼠疫的病原体，武器化的鼠疫耶尔森菌是一种潜在的严重生物恐怖主义制剂。本研究将探索一种罕见的高度抗Y的近交系小鼠品系BALB/cJ。鼠疫这项工作的总体目标是确定这种耐药性的遗传和免疫学基础，这可能为Y。鼠疫感染

DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of bubonic, septicemic and pneumonic plague and represents a serious bioterrorism threat. Most studies on Y. pestis pathogenesis have been directed at identifying and defining the function of the many virulence factors that enable this organism to subvert host defenses. In contrast, relatively few studies have directly examined those immune responses that might be critical for effective host defense against Y. pestis. This proposal takes an unbiased approach aimed at defining the mechanistic basis of resistance of BALB/cJ mice to infection by Y. pestis which appears to be mediated by the early defenses of phagocytes. The first aim of this proposal is to determine the genetic basis of resistance of BALB/cJ mice through classical forward genetic screening and fine mapping of the resistance locus called plague resistance locus 1 (prl1). This analysis will be coupled with phagocyte gene expression data from resistance and susceptible strains. The second aim of this proposal examines BALB/cJ macrophages and neutrophils in vitro for enhanced phagocytic and bactericidal activity as well as resistance to Y. pestis cytotoxicity and apoptosis. Aim 2 will also comparatively examine the bacterial burdens and viability of splenic macrophages and neutrophils at early time points following Y. pestis infection of resistant and susceptible mouse strains. The critical role of neutrophils in BALB/cJ resistance will be assessed though adoptive transfer of these innate immune cells from resistant prl1 strains to susceptible mice. The findings from these studies will not only lead to a better understanding of host defense against Y. pestis in rodent populations, which constitute the major environmental reservoir for this pathogen, but may be generally applicable toward understanding human immunity to this pathogen. The host defenses essential for resistance to Y. pestis are likely to be novel and could define early innate immune targets for therapeutic intervention following infection. PUBLIC HEALTH RELEVANCE: As the causative agent of plague, weaponized Yersinia pestis represents a potentially serious bioterrorism agent. This study will explore an unusual inbred mouse strain called BALB/cJ which is highly resistant to Y. pestis. The overarching goal of this work is to define the genetic and immunologic basis of this resistance which could provide a means for therapeutic intervention following Y. pestis infection.