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

• 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
• 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

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）：抗生素耐药性金黄色葡萄球菌感染正在成为美国和世界各地的主要公共卫生威胁。特别成问题的是 USA300 和 USA400 PFGE 类型的耐甲氧西林金黄色葡萄球菌 (MRSA) 感染，导致坏死性皮肤和肺部感染。虽然在阐明导致感染的 MRSA 毒力因子及其通过群体感应操纵子 agr 的控制方面已经取得了进展，但对于导致易感性的宿主因素却知之甚少。通常，金黄色葡萄球菌会导致高龄和患有严重疾病的人发生机会性感染。然而，USA300 和 USA400 MRSA 感染出现在免疫功能正常的年轻成年人中，这表明以前未被识别的屏障对于控制这些感染至关重要。金黄色葡萄球菌中的群体感应部分由四基因操纵子 agr 调节，其中包括硫内酯肽信息素 (AIP) 和两组分传感器调节器，激活后可对涉及毒力的 160 多个不同基因进行转录控制。我们发现载脂蛋白 B（脂质代谢的一种成分）是侵入性金黄色葡萄球菌皮肤感染的重要屏障，其机制涉及 agr 信号传导的控制。具体来说，apoB 结合并隔离 AIP，从而防止 agr 操纵子的激活。由于皮肤坏死性皮肤感染在这些 MRSA 感染中占主导地位，血浆 apoB 外渗到感染皮肤中可以提供对 agr 的早期控制，从而限制逃避先天免疫杀伤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，包括清道夫受体（例如 CD36）的清除，可能有助于这种宿主防御机制。因此，我们正在测试的假设是，apoB 的氨基末端结构域以及随后通过 CD36 的清除对于宿主防御侵入性 MRSA 感染至关重要。为了检验这一假设，我们将追求以下具体目标： 1) 定义足以在体外结合 AIP 并发挥功能拮抗作用的 apoB 结构域； 2) 确定 apoB 对临床上最相关的社区获得性 MRSA agr 类型菌株的 agr 依赖性侵袭性感染结果的体内贡献：USA300 (agr1) 和 USA400 (agr3)： 3) 确定 CD36 清除 apoB-AIP 复合物对防止 agr 依赖性侵袭性 MRSA 感染的贡献。