Genetic and molecular basis of host resistance to Yersinia pestis.

宿主对鼠疫耶尔森氏菌的抗性的遗传和分子基础。

• 批准号: 8303710
• 负责人: Richard Ian Tapping
• 金额: $ 22.15万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303710
• 关键词: Adoptive Transfer; Apoptosis; BALB/cJ Mouse; Backcrossings; Bioterrorism; Bubonic Plague; Candidate Disease Gene; Cells; Chromosome Mapping; Chromosomes, Human, Pair 17; Complement Inactivators; Congenic Strain; Coupled; Data; Disease Outbreaks; Dominant Genetic Conditions; Emerging Communicable Diseases; Event; Exhibits; Gene Expression; Generations; Genes; Genetic; Genetic Crosses; Genetic Screening; Goals; Growth; Host Defense; Host resistance; Hour; Human; Immune; Immune Targeting; Immune response; Immunity; Immunologics; In Vitro; Inbred BALB C Mice; Inbred Strains Mice; Infection; Inflammatory; Iron; Lead; Liver; Maps; Mediating; Membrane; Membrane Transport Proteins; Modification; Molecular Genetics; Mouse Strains; Mus; Organism; Pathogenesis; Phagocytes; Phagocytosis; Phenotype; Plague; Plasminogen Activator; Play; Pneumonic Plague; Population; Predisposition; Quantitative Trait Loci; Research; Resistance; Resources; Rodent; Role; Screening procedure; Septicemic plague; Signal Transduction; Spleen; Testing; Therapeutic Intervention; Time; Virulence Factors; Work; Yersinia; Yersinia pestis; bactericide; base; capsule; cytotoxicity; genome wide association study; killings; macrophage; meetings; mortality; neutrophil; novel; pathogen; research study; resistance mechanism

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.

描述(申请人提供)：鼠疫耶尔森氏菌是腺鼠疫、败血症和肺鼠疫的病原体，是严重的生物恐怖主义威胁。大多数关于鼠疫杆菌致病机制的研究都是针对确定和确定许多毒力因子的功能，这些毒力因子使这种有机体能够颠覆宿主防御。相比之下，直接检查这些免疫反应的研究相对较少，这些免疫反应可能对宿主有效防御鼠疫至关重要。这一建议采取了一种公正的方法，旨在确定BALB/CJ小鼠对鼠疫杆菌感染的抵抗力的机制基础，这似乎是由吞噬细胞的早期防御调节的。这一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位点1(Prl1)的抗性基因座的精细定位来确定BALB/CJ小鼠的抗性遗传基础。这一分析将是 结合耐药株和敏感株的吞噬细胞基因表达数据。这项建议的第二个目的是在体外检测BALB/CJ巨噬细胞和中性粒细胞的吞噬和杀菌活性，以及对鼠疫杆菌的细胞毒性和细胞凋亡的抵抗力。目的2还将比较检测耐药和敏感品系鼠疫杆菌感染后早期的脾巨噬细胞和中性粒细胞的细菌载量和活性。中性粒细胞在BALB/CJ耐药中的关键作用将通过过继地将这些先天免疫细胞从耐药的prl1株转移到敏感的小鼠身上来评估。这些研究的结果不仅将有助于更好地了解啮齿动物种群对鼠疫杆菌的宿主防御，而啮齿动物种群是这种病原体的主要环境宿主，而且可能普遍适用于了解人类对这种病原体的免疫。对于抵抗鼠疫杆菌至关重要的宿主防御可能是新的，并可能定义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代表着一种潜在的严重的生物恐怖主义因素。这项研究将探索一种不寻常的近亲繁殖小鼠品系，称为BALB/CJ，它对鼠疫杆菌具有高度抗性。这项工作的首要目标是确定这种耐药性的遗传和免疫学基础，这可能为鼠疫杆菌感染后的治疗干预提供一种手段。