Host defense against Staphylococcus aureus skin infections

宿主防御金黄色葡萄球菌皮肤感染

• 批准号: 7651292
• 负责人: Lloyd S Miller
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-07 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651292
• 关键词: Abscess; Accident and Emergency department; Acute suppurative arthritis due to bacteria; Admission activity; Adult; Affect; Air; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteremia; CXCL2 gene; Cells; Cellulitis; Cessation of life; Chemotactic Factors; Chemotaxis; Childhood; Community-Acquired Infections; Cutaneous; DNA; Defect; Development; Endocarditis; Folliculitis; Growth Factor; Hospitals; Host Defense; Host Defense Mechanism; Human; IL8 gene; Impetigo; In Vitro; Incidence; Infection; Infectious Skin Diseases; Interleukin-11; Interleukin-12; Lead; Life; Lifting; Ligands; Lymphangitis; Mediating; Meningitis; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Neutrophil Infiltration; Organ; Organism; Osteomyelitis; Outpatients; Patients; Peptidoglycan; Pharmaceutical Preparations; Play; Pneumonia; Predisposition; Production; Public Health; Reporting; Respiratory Burst; Role; Sepsis; Signal Transduction; Site; Skin; Soft Tissue Infections; Staphylococcus aureus; Time; Toll-like receptors; United States; Vancomycin; Virulent; Visit; antimicrobial; cell type; chemokine; cytokine; fMet-Leu-Phe receptor; human CXCL5 protein; in vitro Model; in vivo; insight; keratinocyte; lipoteichoic acid; methicillin resistant Staphylococcus aureus; neutrophil; pathogen; receptor; resistant strain; response

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to gain insight into mechanisms of cutaneous host defense against the common bacterial skin pathogen Staphylococcus aureus. S. aureus is responsible for the vast majority of skin and soft tissue infections such as impetigo, folliculitis, and cellulitis. In addition, S. aureus can often spread from the skin and lead to invasive and frequently life-threatening infections such as lymphangitis, septic arthritis, osteomyelitis, bacteremia, pneumonia, abscesses of various organs, meningitis, endocarditis, and sepsis. Despite advances in conventional antibiotic therapy, the incidence of S. aureus infections have continued to increase and many hospital- and community-acquired infections have been complicated by the widespread emergence of antibiotic resistant strains. These strains include methicillin-resistant S. aureus (MRSA), multi-drug resistant strains, and even strains that are resistant to vancomycin, the last drug to which the organism used to be uniformly sensitive. These resistant strains have become a significant public health problem causing not only morbidity but even deaths in previously healthy adult and pediatric patients. In time, without the development of new and effective antibacterial therapies, it is possible that multi-drug resistant S. aureus strains will be untreatable by conventional antibiotics. In the present proposal, we plan to investigate the mechanisms involved in host defense and neutrophil recruitment against S. aureus infections in the skin, where most of these infections originate. The recruitment of neutrophils to the site of infection is the first line of defense against S. aureus infection and is also required for elimination of the pathogen. Our recent findings demonstrate that activation of IL-1R-signaling by resident skin cells is critical for recruitment of neutrophils to a site of S. aureus infection in the skin. Since IL-1R is activated by IL-11 and IL-12, we hypothesize that either or both of these cytokines are important in promoting neutrophil recruitment in vivo. We further hypothesize that activation of Toll like receptors (TLRs) may lead to production of IL-11 and IL-12 and also promote neutrophil recruitment. We propose to investigate the mechanisms that promote IL-1R-mediated neutrophil recruitment by using an in vivo mouse cutaneous infection model and in vitro human organotypic keratinocyte cultures. This proposal should provide important new insights into mechanisms of cutaneous host defense against bacterial pathogens. We believe that this study is timely and relevant since the incidence of S. aureus infections is increasing and the treatment of these infections has become exceedingly difficult due to the emergence of antibiotic resistant strains. RELEVANCE TO PUBLIC HEALTH Staphylococcus aureus skin infections are a significant public health problem resulting in 11.6 million outpatient and emergency room visits and 464,000 hospital admissions per year in the U.S. In the present proposal, we plan to investigate mechanisms of neutrophil recruitment against S. aureus skin infection in the skin, where most of S. aureus infections originate. We believe that this proposal is timely and relevant, because the incidence of S. aureus skin infections is increasing and hospital- and community-acquired infections caused by methicillin-resistant S. aureus (MRSA) and multi-drug resistant strains have emerged as major public health threats in the United States.

描述（由申请人提供）： 该提案的长期目标是深入了解皮肤宿主针对常见细菌皮肤病原体金黄色葡萄球菌的防御机制。金黄色葡萄球菌是绝大多数皮肤和软组织感染的罪魁祸首，例如脓疱疮、毛囊炎和蜂窝织炎。此外，金黄色葡萄球菌通常可以从皮肤传播并导致侵袭性且经常危及生命的感染，例如淋巴管炎、化脓性关节炎、骨髓炎、菌血症、肺炎、各种器官脓肿、脑膜炎、心内膜炎和败血症。尽管传统抗生素治疗取得了进展，但金黄色葡萄球菌感染的发病率仍在持续增加，并且由于抗生素耐药菌株的广泛出现，许多医院和社区获得性感染变得更加复杂。这些菌株包括耐甲氧西林金黄色葡萄球菌 (MRSA)、多重耐药菌株，甚至对万古霉素耐药的菌株，万古霉素是生物体过去一致敏感的最后一种药物。这些耐药菌株已成为一个重大的公共卫生问题，不仅导致先前健康的成人和儿童患者发病，甚至死亡。随着时间的推移，如果不开发出新的有效的抗菌疗法，传统抗生素可能无法治疗多重耐药金黄色葡萄球菌菌株。在本提案中，我们计划研究涉及宿主防御和中性粒细胞募集以抵抗皮肤金黄色葡萄球菌感染的机制，而皮肤中的金黄色葡萄球菌感染是大多数感染的起源。中性粒细胞募集到感染部位是抵抗金黄色葡萄球菌感染的第一道防线，也是消除病原体所必需的。我们最近的研究结果表明，常驻皮肤细胞激活 IL-1R 信号对于将中性粒细胞募集到皮肤金黄色葡萄球菌感染部位至关重要。由于 IL-1R 被 IL-11 和 IL-12 激活，我们假设这些细胞因子中的一种或两种对于促进体内中性粒细胞募集很重要。我们进一步假设 Toll 样受体 (TLR) 的激活可能导致 IL-11 和 IL-12 的产生，并促进中性粒细胞募集。我们建议通过使用体内小鼠皮肤感染模型和体外人器官型角质形成细胞培养物来研究促进 IL-1R 介导的中性粒细胞募集的机制。该提案应该为皮肤宿主防御细菌病原体的机制提供重要的新见解。我们相信这项研究是及时且相关的，因为金黄色葡萄球菌感染的发病率正在增加，并且由于抗生素耐药菌株的出现，这些感染的治疗变得极其困难。与公共卫生的相关性 金黄色葡萄球菌皮肤感染是一个重大的公共卫生问题，在美国每年导致 1,160 万人次门诊和急诊就诊以及 464,000 人入院。在本提案中，我们计划研究针对金黄色葡萄球菌皮肤的中性粒细胞募集机制皮肤感染，大多数金黄色葡萄球菌感染源自皮肤。我们认为这一建议是及时且相关的，因为金黄色葡萄球菌皮肤感染的发病率正在增加，并且由耐甲氧西林金黄色葡萄球菌（MRSA）和多重耐药菌株引起的医院和社区获得性感染已成为主要感染源。美国的公共卫生威胁。