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: 8422971
• 负责人: Richard Ian Tapping
• 金额: $ 18.6万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422971
• 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; 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; screening

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.

描述（由申请人提供）：耶尔森氏菌是Bubonic，svesic症和肺炎瘟疫的病因，代表了严重的生物恐怖威胁。大多数关于鼠疫发病机理的研究都致力于识别和定义许多毒力因子的功能，从而使该生物体颠覆宿主防御。相比之下，相对较少的研究直接检查了那些对有效宿主防御Y. Pestis至关重要的免疫反应。该提案采用了一种公正的方法，旨在定义BALB/CJ小鼠对Y. Pestis感染的抗性的机理基础，该方法似乎是由吞噬细胞的早期防御剂介导的。该提案的第一个目的是通过经典的正向遗传筛选和称为瘟疫抗性基因座1（PRL1）的抗性基因座的精细映射来确定BALB/CJ小鼠抗性的遗传基础。该分析将是 结合来自耐药性和易感性菌株的吞噬细胞基因表达数据。该提案的第二个目的是在体外检查BALB/CJ巨噬细胞和中性粒细胞，以增强吞噬性和杀菌活性，以及​​对鼠疫耶和华的耐药性。 AIM 2还将在Y. pestis感染后，在早期的耐药和易感小鼠菌株后，在早期时间点脾巨噬细胞和中性粒细胞的细菌负担和生存能力。尽管这些先天免疫细胞从耐药性PRL1菌株转移到易感小鼠时，将评估中性粒细胞在BALB/CJ抗性中的关键作用。这些研究的发现不仅会更好地理解啮齿动物种群中对Y. Pestis的宿主防御，这是该病原体的主要环境储层，而且通常适用于了解人类对这种病原体的免疫力。抗孕妇抵抗的宿主防御可能是新颖的，并且可以定义感染后治疗干预的早期先天免疫靶标。