Antioxidant-based mechanisms used by staphyloccocus aureus to evade host defenses

金黄色葡萄球菌利用基于抗氧化的机制来逃避宿主防御

• 批准号: 7922069
• 负责人: George Y Liu
• 金额: $ 38.6万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922069
• 关键词: Address; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antioxidants; Attenuated; Bacteria; Beta Carotene; Biological Assay; Biology; Carotene; Development; Disease; Drug Industry; Effector Cell; Enzymes; Foundations; Goals; Health; Hospitals; Host Defense; Human; Hydrogen Peroxide; Immune; Infection; Inflammation; Inflammatory; Invaded; Investigation; Knowledge; Lead; Methods; Modeling; Molecular; Molecular Genetics; Mus; Nuclear Receptors; Oxidants; Oxidation-Reduction; Pathogenesis; Pathway interactions; Phagocytes; Pigments; Principal Investigator; Property; Public Health; Reactive Oxygen Species; Regulation; Research; Respiratory Burst; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Skin; Societies; Species Specificity; Staphylococcal Infections; Staphylococcus aureus; Steroids; Streptococcus Group B; System; Systemic infection; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Up-Regulation; Virulence; Work; alkyl hydroperoxide reductase C; antimicrobial; attenuation; base; catalase; community setting; defined contribution; inhibitor/antagonist; innovation; killings; microbial; microbicide; microorganism; mutant; novel; novel therapeutic intervention; pathogen; prevent; programs; quorum sensing; second messenger; staphyloxanthin; tool

DESCRIPTION (provided by applicant): Staphylococcus aureus is an important pathogen and a major public health concern both in hospital and community settings. A central determinant of health or disease during staphylococcal infection is the host and bacterial antioxidant and redox systems. The phagocyte oxidative burst defends the host by generating reactive oxygen species (ROS) that are directly toxic to invading microorganisms, but ROS also serve as second messengers in key inflammatory signaling networks, and interfere with S. aureus virulence upregulation. S. aureus opposes this strategy by inactivating ROS using specific antioxidants. In this proposal, we hypothesize that the bacterial antioxidants function more than just a shield, and act to block host pro-inflammatory signaling through quenching of second messengers, and-inactivate ROS to minimize host interference with bacterial virulence. By implication, combined targeting of these bacterial enzymes could severely attenuate Staphylococcal virulence while providing a boost to the host immune defense. Our recent virulence studies have identified staphyloxanthin as an important antioxidant product upregulated during S. aureus pathogenesis (Liu et al. JEM 2005). Extending on this theme, our proposed research will investigate using molecular Koch's postulate the virulence and antioxidant functions of two additional S. aureus antioxidants, catalase and alkyl hydroperoxide reductase C (AhpC). In Specific Aim #1, we will define the contribution of catalase and AhpC to S. aureus virulence using molecular genetic methods. In Specific Aim #2, we will assess whether staphylococcal antioxidants modulate inflammatory signaling in phagocytes or prevent host manipulation of bacterial virulence. In Specific Aim #3 we will explore therapeutic approaches that target expression or function of these antioxidant products. Significance: The proposed research will address fundamental questions about S. aureus-host interaction, and uncover novel therapeutic approaches toward treatment of S. aureus diseases.

描述（由申请人提供）：金黄色葡萄球菌是一种重要的病原体，是医院和社区环境中主要的公共卫生问题。在葡萄球菌感染期间，健康或疾病的主要决定因素是宿主和细菌的抗氧化和氧化还原系统。吞噬细胞的氧化爆发通过产生对入侵微生物具有直接毒性的活性氧（ROS）来保护宿主，但ROS也在关键的炎症信号网络中充当第二信使，并干扰金黄色葡萄球菌毒力上调。金黄色葡萄球菌通过使用特定的抗氧化剂灭活ROS来反对这种策略。在这项提议中，我们假设细菌抗氧化剂的功能不仅仅是一个盾牌，而且通过淬火第二信使来阻断宿主的促炎信号，并灭活ROS以减少宿主对细菌毒力的干扰。这意味着，这些细菌酶的联合靶向可以严重减弱葡萄球菌的毒力，同时增强宿主的免疫防御。

项目成果

Intranasal application of S. epidermidis prevents colonization by methicillin-resistant Staphylococcus aureus in mice.

• DOI: 10.1371/journal.pone.0025880
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Park B;Iwase T;Liu GY
• 通讯作者: Liu GY

Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection.

• DOI: 10.1371/journal.ppat.1005292
• 发表时间: 2015
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Tseng CW;Biancotti JC;Berg BL;Gate D;Kolar SL;Müller S;Rodriguez MD;Rezai-Zadeh K;Fan X;Beenhouwer DO;Town T;Liu GY
• 通讯作者: Liu GY

Staphylococcus aureus Panton-Valentine leukocidin targets muscle tissues in a child with myositis and necrotizing fasciitis.

金黄色葡萄球菌潘顿-瓦伦丁杀白细胞素针对患有肌炎和坏死性筋膜炎的儿童的肌肉组织。

• DOI: 10.1086/649217
• 发表时间: 2010
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Lehman,Deborah;Tseng,ChingWen;Eells,Samantha;Miller,LorenG;Fan,Xuemo;Beenhouwer,DavidO;Liu,GeorgeY
• 通讯作者: Liu,GeorgeY

Staphylococcus aureus Panton-Valentine leukocidin contributes to inflammation and muscle tissue injury.

• DOI: 10.1371/journal.pone.0006387
• 发表时间: 2009-07-27
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Tseng CW;Kyme P;Low J;Rocha MA;Alsabeh R;Miller LG;Otto M;Arditi M;Diep BA;Nizet V;Doherty TM;Beenhouwer DO;Liu GY
• 通讯作者: Liu GY

Molecular pathogenesis of Staphylococcus aureus infection.

• DOI: 10.1203/pdr.0b013e31819dc44d
• 发表时间: 2009-05
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Liu GY