Host defense against Staphylococcus aureus skin infections

描述(由申请人提供)： 这项建议的长期目标是深入了解皮肤宿主对常见皮肤细菌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，如脓疱病、毛囊炎和蜂窝组织炎。此外，金黄色葡萄球菌经常从皮肤传播，导致侵袭性感染，经常危及生命，如淋巴管炎、感染性关节炎、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。尽管在常规抗生素治疗方面取得了进展，但金黄色葡萄球菌感染的发生率仍在继续增加，许多医院和社区获得的感染因抗生素耐药菌株的广泛出现而变得更加复杂。这些菌株包括耐甲氧西林金黄色葡萄球菌(MRSA)、多药耐药菌株，甚至对万古霉素耐药的菌株，万古霉素是微生物过去一致敏感的最后一种药物。这些耐药菌株已经成为一个重大的公共卫生问题，不仅导致以前健康的成人和儿童患者的发病率，甚至造成死亡。随着时间的推移，如果没有新的有效的抗菌疗法的开发，多药耐药的金黄色葡萄球菌菌株可能无法用传统的抗生素治疗。在目前的提案中，我们计划研究宿主防御和中性粒细胞募集所涉及的机制，以对抗皮肤中金黄色葡萄球菌的感染，这些感染大多起源于皮肤。中性粒细胞聚集到感染部位是抵御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。我们最近的发现表明，常驻皮肤细胞激活IL-1R信号对于中性粒细胞在皮肤中金黄色葡萄球菌感染部位的募集至关重要。由于IL-1R是由IL-11和IL-12激活的，我们推测这两种细胞因子中的一种或两种在促进体内中性粒细胞募集中起重要作用。我们进一步假设，Toll样受体(TLRs)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。我们建议通过体内小鼠皮肤感染模型和体外培养的人器官型角质形成细胞来研究促进IL-1R介导的中性粒细胞募集的机制。这一建议将为皮肤宿主防御细菌病原体的机制提供重要的新见解。我们认为，这项研究是及时和相关的，因为金黄色葡萄球菌感染的发生率正在增加，而且由于出现了抗生素耐药菌株，这些感染的治疗变得非常困难。与公共卫生相关的金黄色葡萄球菌皮肤感染是一个重大的公共卫生问题，导致美国每年有1160万门急诊室就诊和46.4万人住院。在当前的提案中，我们计划研究中性粒细胞募集对皮肤中金黄色葡萄球菌皮肤感染的作用机制，皮肤是大多数金黄色葡萄球菌感染的发源地。我们认为这项建议是及时和相关的，因为金黄色葡萄球菌皮肤感染的发生率正在增加，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美国主要的公共卫生威胁。

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.