Genetic and molecular basis of host resistance to Yersinia pestis.

描述（由申请人提供）：鼠疫耶尔森菌是腺鼠疫、败血症鼠疫和肺鼠疫的病原体，是严重的生物恐怖主义威胁。大多数关于鼠疫杆菌发病机制的研究都是针对识别和定义许多毒力因子的功能，这些毒力因子使这种生物能够破坏宿主的防御。相比之下，相对较少的研究直接检查了那些可能对宿主有效防御鼠疫杆菌至关重要的免疫反应。本研究采用公正的方法，旨在确定BALB/cJ小鼠对鼠疫杆菌感染的抗性机制基础，这似乎是由吞噬细胞的早期防御介导的。本研究的第一个目的是通过经典的正向遗传筛选和鼠疫抗性位点1 （prl1）的精细定位，确定BALB/cJ小鼠抗性的遗传基础。这个分析将是

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.