Apolipoprotein B and Control of S. aureus Quorum Sensing

载脂蛋白 B 和金黄色葡萄球菌群体感应的控制

基本信息

批准号：
8501792
负责人：
Pamela Ranel Hall
金额：
$ 2.95万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501792
关键词：
Adult Age Antibiotic Resistance Apolipoproteins B Bacteria Binding Binding Sites Bone Marrow CD36 gene Cell physiology Communities Complex Critical Illness Extravasation Gene Expression Genes Genetic Polymorphism Goals Hemolysin Hospitals Host Defense Host Defense Mechanism Human Immune Immunocompetent In Vitro Incidence Infection Infection Control Infectious Skin Diseases Integration Host Factors Link Lipoproteins Low-Density Lipoproteins Lung Medical Metabolism Molecular Molecular Conformation Mus Natural Immunity Necrosis Operon Opportunistic Infections Outcome Patients Peptide Hydrolases Peptides Pheromone Plasma Predisposition Process Production Proteolysis Public Health Publishing Pulsed-Field Gel Electrophoresis Replacement Therapy Role Signal Transduction Skin Staphylococcus aureus Structural Protein Testing Toxin Transcriptional Regulation Up-Regulation Very low density lipoprotein Virulence Virulence Factors Virulent Woman Work apolipoprotein B-100 bactericide clinically relevant crosslink in vivo killings lipid metabolism macrophage men methicillin resistant Staphylococcus aureus prevent quorum sensing scavenger receptor sensor uptake

项目摘要

DESCRIPTION (provided by applicant): Antibiotic resistant Staphylococcus aureus infections are emerging as a major public health threat in the US and around the world. Particularly problematic are methicillin resistant S. aureus (MRSA) infections of the USA300 and USA400 PFGE types that cause necrotic skin and lung infections. While progress has been made in elucidating the MRSA virulence factors that contribute to infection and their control by a quorum sensing operon, agr, very little is known about host factors that contribute to susceptibility. Typically, S. aureus causes opportunistic infections in those at the extremes of age and with serious medical conditions. However, USA300 and USA400 MRSA infections are presenting in young immunocompetent adults suggesting that barriers previously unrecognized are essential to control these infections. Quorum sensing in S. aureus is regulated in part by a four gene operon, agr, which includes a thiolactone peptide pheromone (AIP) and a two component sensor regulator that upon activation leads to transcriptional control of over 160 different genes involved in virulence. We identified apolipoprotein B, a component of lipid metabolism, as an essential barrier to invasive S. aureus skin infection and that the mechanism involves control of agr signaling. Specifically, apoB binds to and sequesters AIP thus preventing activation of the agr operon. Because dermonecrotic skin infections predominate in these MRSA infections, extravasation of plasma apoB into infected skin could provide early control of agr and thus limit the production of virulence factors required to evade innate immune killing and clearance of the bacteria. Because apoB is the major structural protein of both VLDL and LDL, aspects of lipoprotein metabolism, including clearance by scavenger receptors (e.g. CD36), could contribute to this host defense mechanism. Therefore, the hypothesis we are testing is that the amino terminal domain of apoB and subsequent clearance through CD36 are essential for host defense against invasive MRSA infection. To test this hypothesis we will pursue the following specific aims: 1) To define the domain(s) of apoB sufficient for binding and functional antagonism of AIP in vitro; 2) To determine the in vivo contribution of apoB to the outcome of agr-dependent invasive infections of strains from the most clinically relevant community-acquired MRSA agr types: USA300 (agr1) and USA400 (agr3): 3) To determine the contribution of CD36 clearance of apoB-AIP complexes to protection against agr dependent invasive MRSA infections.

描述（由申请人提供）：金黄色葡萄球菌感染的抗生素抗生素正在成为美国和世界各地的主要公共卫生威胁。尤其有问题的是耐甲氧西林的金黄色葡萄球菌（MRSA）感染的USA300和USA400 PFGE类型，引起坏死皮肤和肺部感染。尽管已经取得了进展，但在阐明了有助于感染的MRSA毒力因子及其控制因素的控制因素，而群体感应操纵子AGR对宿主因子有助于敏感性的众所周知。通常，金黄色葡萄球菌会在年龄极端和严重的医疗状况下引起机会感染。但是，在年轻的免疫能力成年人中提出了USA300和USA400 MRSA感染，这表明以前未被认可的障碍对于控制这些感染至关重要。金黄色葡萄球菌中的法定感测受四个基因操纵子AGR的一部分调节，其中包括硫代酮肽信息素（AIP）和两个组分传感器调节剂，该传感器调节剂在激活后会导致超过160种涉及毒力的不同基因的转录控制。我们确定脂肪蛋白B（脂质代谢的一个成分）是侵入性金黄色葡萄球菌感染的基本障碍，并且该机制涉及控制AGR信号传导。具体而言，APOB与AIP结合并隔离AIP，从而防止了AGR操纵子的激活。由于皮肤皮肤感染在这些MRSA感染中占主导地位，因此血浆APOB渗入受感染的皮肤可以提供早期控制AGR，因此限制了逃避先天免疫杀死和清除细菌所需的毒力因子的产生。由于APOB是VLDL和LDL的主要结构蛋白，因此脂蛋白代谢的各个方面（包括清除剂受体清除率（例如CD36））可能有助于这种宿主防御机制。因此，我们正在检验的假设是，APOB的氨基末端结构域以及随后通过CD36的清除率对于抵抗入侵MRSA感染的宿主防御至关重要。为了检验这一假设，我们将追求以下特定目的：1）定义足以在体外结合和功能拮抗作用的APOB的域； 2）确定APOB对AGR依赖性侵入性感染的体内贡献，来自最临床相关的社区获得的MRSA AGR类型：USA300（AGR1）和USA400（AGR3）：3），以确定对APOB-AIP复合物对APOB-AIP COFFFELKS对APOB-APOB的贡献的贡献。