Epidemic CA-MRSA: Molecular Epidemiology and Immunology

描述（由申请人提供）：我们建议使用DMID资助的“克林霉素、甲氧苄啶-磺胺甲恶唑或安慰剂治疗社区相关耐甲氧西林金黄色葡萄球菌（CA-MRSA）引起的无并发症皮肤和软组织感染的随机、双盲试验”中招募的患者进行研究。“NIAID与芝加哥大学的Co-PI以及加州大学/弗朗西斯科分校、加州大学/洛杉矶分校的调查人员签订的这份合同，为探索未解决的问题提供了一个独特的机会。大约375名患有皮肤和软组织感染（SI）的儿童和成人将在芝加哥大学接受为期三年的研究。初步数据表明，大约84%的注册者将有一个S。金黄色葡萄球菌SI，提供了一个独特的机会，进行额外的研究，解决的根本原因增加敏感性的SI在一般人群。在过去的十年中，MRSA感染的发病率和频率呈指数级增加，特别是在其他健康个体中，CA-MRSA在美国已经成为流行病，现在是公共卫生的当务之急。认识到CA-MRSA菌株可以迅速传播并引起严重疾病，需要进行紧急调查，以了解分子微生物致病性和潜在的宿主免疫反应。因此，我们组建了一个由微生物学家、传染病专家和免疫学家组成的多学科团队，同时探索可能对CA-MRSA流行病生物学产生重要见解的几个领域，重点关注宿主免疫反应在CA-MRSA感染中的作用。本提案中详细介绍的研究将为宿主先天和适应机制对感染易感性的贡献提供实质性的见解。希望新的信息将指导新的治疗和预防策略，以打击CA-MRSA感染。 公共卫生相关性：认识到社区相关的耐甲氧西林金黄色葡萄球菌（CA-MRSA）可以迅速传播，并导致严重的皮肤感染的任务，需要紧急调查的分子微生物致病性和宿主免疫反应，有助于这种流行病。DMID将合同授予芝加哥大学的合作PI，以比较急诊科皮肤感染的治疗策略。在这些辅助研究中，我们建议确定是否增加易感性CA-MRSA皮肤感染的一个子集的人口是由于固有缺陷的主机先天性和T细胞免疫反应和/或CA-MRSA的特定属性，以调节免疫反应。

DESCRIPTION (provided by applicant): We are proposing studies utilizing the patients enrolled in the DMID-funded "Randomized, Double-Blind Trial of Clindamycin, Trimethoprim-Sulfamethoxazole, or Placebo for Uncomplicated Skin and Soft Tissue Infections Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA)." This contract by NIAID to the Co-PI at the University of Chicago as well as investigators at the University of California/San Francisco, Harbor-University of California/Los Angeles, has provided a unique opportunity to explore unaddressed issues. About 375 children and adults with skin and soft tissue infections (SIs) will be enrolled for a period of three years at the University of Chicago. Preliminary data indicate that about 84% of enrollees will have a S. aureus SI, providing a unique opportunity to perform additional research addressing the underlying cause for increased susceptibility to SIs in the general population. In the last decade the incidence and frequency of MRSA infections has increased exponentially, particularly among otherwise healthy individuals, to the extent that CA-MRSA has become epidemic in the US and is now a public health imperative. The recognition that CA-MRSA strains can both spread rapidly and cause severe disease mandates a need for urgent investigation to understand the molecular microbial pathogenicity and underlying host immune responses. Accordingly, we have assembled a multidisciplinary team of microbiologists, infectious disease experts, and immunologists to explore simultaneously several areas likely to yield important insights into the biology of the CA-MRSA epidemic, with a focus on the role of host immune responses in CA-MRSA infection. Studies detailed in this proposal will provide substantial insight into the contributions of host innate and adaptive mechanisms to infection susceptibility. It is hoped that new information will guide novel therapeutic and preventive strategies to combat CA-MRSA infection. PUBLIC HEALTH RELEVANCE: The recognition that community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can both spread rapidly and cause severe skin infections mandates a need for urgent investigation of the molecular microbial pathogenicity and host immune responses contributing to this epidemic. A contract was awarded by DMID to the co-PI at the University of Chicago to compare treatment strategies in skin infections in the Emergency Department. In these ancillary studies, we propose to determine whether increased susceptibility to CA-MRSA skin infections by a subset of the population is due to inherent defects in host innate and T cell immune responses and/or to specific properties of CA-MRSA to modulate immune responses.