Bacterial Interference to Prevent Staphylococcus aureus Infection

项目摘要 虽然金黄色葡萄球菌是一种主要的人类病原体， 由于疾病负担，我们几乎没有预防感染或控制其 传播.在20世纪60年代，普遍的做法是用相对较低的 良性S.金黄色葡萄球菌称502 A是一项战略，以打击爆发更多的 毒性葡萄球菌菌株，这种做法被称为细菌干扰。 数千名新生儿暴露于502 A，几乎没有相关的发病率， 死亡率，但尽管其相对良好的安全记录，实践中被放弃， 1970年，出于安全考虑。细菌干扰的基本机制是 从未调查过。我们最近发现，502 A激发了一种非常不同的细胞因子， 与其他流行病和强毒株相比，虽然它的侵入性较小， 暴露于502 A的宿主细胞具有增加的I型干扰素水平以及几种 其它促炎细胞因子（例如，TNF α，IL-6）相比，暴露于其他S. 金黄色葡萄球菌我们假设S.刺激502 A样的金黄色葡萄球菌菌株 免疫应答通过以下方式保护免于定植和随后的感染： 诱导免疫系统排斥其他菌株。了解机制 502 A细菌干扰可以让我们设计策略， 定植和感染毒性或抗生素抗性菌株。还可能导致 非殖民化战略的设置经常性的S。金黄色葡萄球菌感染或 使用抗菌剂进行普遍去殖民化的护理单位已被证明， 降低死亡率。我们联合收割机将临床方法与基础分子研究相结合， 旨在评估细菌干扰策略在临床环境中的可行性。 该研究小组整合了临床S。金黄色葡萄球菌流行病学，宿主先天性 免疫学、基因组学和微生物组学研究。目标1利用自然多样性， S.在人群中发现的金黄色葡萄球菌菌株，以前瞻性地评估 502 A样菌株的定殖和可能的保护。目标2使用模型系统 为了评估免疫系统对502 A样菌株的反应以及它们的 保护作用。目的3检验使用毒力减毒菌株的可能性 进行细菌干扰和去殖民化。

PROJECT SUMMARY Although Staphylococcus aureus is a major human pathogen that causes an enormous burden of disease, we have very few strategies for preventing infection or controlling its spread. In the 1960's it was a widespread practice to inoculate neonates with a relatively benign strain of S. aureus called 502A as a strategy to combat outbreaks of more virulent staphylococcal strains, a practice referred to as bacterial interference. Thousands of neonates were exposed to 502A with very little associated morbidity and mortality, but despite its relatively good safety record, the practice was abandoned in the 1970's due to safety concerns. The basic mechanisms of bacterial interference were never investigated. We recently showed that 502A elicits a very different cytokine response compared to other epidemic and virulent strains. Although it is less invasive, host cells exposed to 502A have increased levels of type I Interferons as well as several other proinflammatory cytokines (eg., TNFa, IL-6) compared to exposure to other S. aureus strains. Our hypothesis is that S. aureus strains that stimulate 502A-like immune responses protect from colonization and subsequent infection by inducing the immune system to reject other strains. Understanding the mechanism of 502A bacterial interference could allow us to design strategies for protection against colonization and infection with virulent or antibiotic resistant strains. It may also lead to strategies for decolonization in the setting of recurrent S. aureus infection or in intensive care units where universal decolonization using antimicrobials has been show to decrease mortality. We combine a clinical approach with basic molecular research, aiming to assess the feasibility of a bacterial interference strategy in the clinical context. The study team integrates expertise in clinical S. aureus epidemiology, host innate immunology, and genomics and microbiome studies. Aim 1 uses the natural diversity in S. aureus strains found in human populations to prospectively assess the correlation of colonization with 502A-like strains and possible protection. Aim 2 uses model systems to assess the response of the immune system to 502A-like strains as well as their protective effect. Aim 3 examines the possibility of using a virulence-attenuated strain for bacterial interference and decolonization.