Epidemic CA-MRSA: Molecular Epidemiology and Immunology

描述(由申请人提供)：我们建议利用DMID资助的“克林霉素、甲氧嘧啶-磺胺甲恶唑或安慰剂的随机双盲试验”中登记的患者进行研究，以治疗由社区相关的耐甲氧西林金黄色葡萄球菌(CA-MRSA)引起的无并发症的皮肤和软组织感染。NIAID将这份合同交给芝加哥大学的Co-Pi以及加州大学/旧金山、港湾-加州大学/洛杉矶的调查人员，这为探索未解决的问题提供了一个独特的机会。芝加哥大学将招收约375名患有皮肤和软组织感染(SIS)的儿童和成人，为期三年。初步数据显示，大约84%的参与者将患有金黄色葡萄球菌感染，这提供了一个独特的机会，可以进行进一步的研究，解决普通人群中SIS易感性增加的根本原因。在过去的十年中，MRSA感染的发生率和频率呈指数级增长，特别是在其他健康的人中，以至于CA-MRSA在美国已经流行，现在是公共卫生的当务之急。认识到CA-MRSA菌株既可以迅速传播，又可以导致严重疾病，因此迫切需要进行研究，以了解分子微生物的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，同时探索几个可能对CA-MRSA流行的生物学产生重要见解的领域，重点是宿主免疫反应在CA-MRSA感染中的作用。这项建议中详细的研究将对宿主先天和适应机制对感染易感性的贡献提供实质性的洞察。希望新的信息将指导新的治疗和预防策略，以对抗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，因此迫切需要研究导致这种流行病的分子微生物致病性和宿主免疫反应。DMID将一份合同授予芝加哥大学的联合PI，以比较急诊科皮肤感染的治疗策略。在这些辅助研究中，我们建议确定是否部分人群对CA-MRSA皮肤感染的易感性增加是由于宿主固有的缺陷和T细胞免疫反应和/或CA-MRSA调节免疫反应的特定特性所致。

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.