Salmonella Antimicrobial Peptide Resistance

沙门氏菌抗菌肽耐药性

基本信息

批准号：
7767666
负责人：
JOHN S GUNN
金额：
$ 33.41万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7767666
关键词：
Address Affect Antimicrobial Resistance Area Bacteria Bacterial Infections Cell Survival Cells Clinical Detection Divalent Cations Environment Epithelial Epithelial Cells Fever Gastroenteritis Gene Expression Gene Expression Regulation Genes Genetic Host Defense Human Immune Immune response Immune system In Vitro Infection Inflammatory Intestinal Mucosa Intestines Knock-in Mouse Knock-out Knowledge Laboratories Lead Light Lipid A Lipopolysaccharides Location Mass Spectrum Analysis Mediating Membrane Methods Modification Morbidity - disease rate Mouse Strains Mus Organism Outcome Pathogen detection Pathogenesis Peptides Phagocytes Phenotype Play Predisposition Proteins Regulon Research Resistance Resolvase Role Salmonella Salmonella enterica Salmonella typhi Salmonella typhimurium Signal Transduction Structure of aggregated lymphoid follicle of small intestine Surface System Technology Typhoid Fever Virulence Work antimicrobial peptide base cytokine in vivo intestinal epithelium killings mortality mutant novel therapeutic intervention oral infection pathogen public health relevance response sensory mechanism toll-like receptor 4 tool

项目摘要

DESCRIPTION (provided by applicant): Salmonella spp. are a cause of significant worldwide morbidity and mortality. These organisms primarily cause two clinical manifestations: typhoid fever and gastroenteritis. During oral infection, salmonellae interact with the host innate immune system within the gut and, after passing through the intestinal epithelial barrier, within host cells. A key component of the innate immune system in these locations are antimicrobial peptides (APs): ubiquitous proteins that destroy bacterial membranes. PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are Salmonella spp. two-component regulatory systems (TCSs) that detect host signals and/or activate genes during infection. One signal these systems have been shown to sense in vitro are APs, and this sensing leads to modification of the lipopolysaccharide that covers the bacterial surface. An outcome of these modifications is increased resistance to AP-mediated killing. While much is known in vitro about the signals that activate these TCSs and the phenotypes that result from PhoPQ and PmrAB induction, little is known about the in vivo signals or about the role that PmrAB-mediated LPS modifications play in altering the innate immune response. Thus we will pursue the hypotheses that APs are an in vivo activating signal and that the LPS modifications that protect against AP killing also dampen multiple aspects of the innate immune response. Furthermore, we will investigate the PmrAB TCS and its function in the strict human pathogen Salmonella enterica serovar Typhi, where this important regulatory system has been poorly characterized. These studies will provide a greater understanding of the adaptation of salmonellae to the in vivo environment and shed light on ways to interfere with in vivo induced mechanisms of pathogenesis. PUBLIC HEALTH RELEVANCE: Salmonella spp. are a cause of significant worldwide morbidity and mortality. During infection, the bacterium senses and responds to host derived signals. In sensing this environment, the bacterium modifies its surface to aid survival in the harsh host milieu. Our proposed work will uncover new therapeutic approaches through a better understanding of these important Salmonella sensory mechanisms.

描述（由申请人提供）：沙门氏菌属。是全球发病率和死亡率重大的原因。这些生物主要引起两种临床表现：伤寒和胃肠炎。在口腔感染期间，沙门氏菌与肠道内的宿主先天免疫系统相互作用，并在穿过肠上皮屏障后，在宿主细胞内相互作用。在这些位置，先天免疫系统的关键组成部分是抗菌肽（APS）：无处不在的蛋白质，破坏细菌膜。 Phop-Phoq（PhOPQ）和PMRA-PMRB（PMRAB）是沙门氏菌属。在感染过程中检测宿主信号和/或激活基因的两组分组调节系统（TCSS）。这些系统已被证明是在体外感知的，是AP，这种传感导致覆盖细菌表面的脂多糖的修饰。这些修饰的结果是增加了对AP介导的杀戮的抵抗力。尽管在体外众所周知，激活这些TCS的信号以及由PHOPQ和PMRAB诱导引起的表型，但对体内信号或PMRAB介导的LPS修饰在改变先天免疫反应中起着作用的作用知之甚少。因此，我们将提出以下假设：AP是一个体内激活信号，并且防止AP杀死的LPS修饰也抑制了先天免疫反应的多个方面。此外，我们将研究PMRAB TCS及其在严格的人类病原体肠道血清中的功能，在这种情况下，这种重要的调节系统的特征很差。这些研究将对沙门氏菌对体内环境的适应性的适应有了更大的了解，并阐明了干扰体内诱导的发病机理的方法。公共卫生相关性：沙门氏菌属。是全球发病率和死亡率重大的原因。在感染过程中，细菌感官并响应宿主派生信号。在感知这种环境时，细菌会修饰其表面以帮助苛刻的宿主环境中的生存。我们提出的工作将通过更好地理解这些重要的沙门氏菌感官机制来揭示新的治疗方法。