Investigating the relationship between antibiotics and nosocomial pneumonia.

项目摘要 肺炎造成的死亡人数比世界上任何其他传染病都多。耐甲 金黄色葡萄球菌（MRSA）是医院获得性肺炎最常见的原因之一。的 MRSA的流行在全球范围内不断增加。为了应对日益严重的MRSA问题，我们需要更大的 了解感染期间宿主-病原体相互作用。这一点仍然知之甚少，部分原因是 缺乏与医疗机构中发生的感染相关的体内模型。迄今为止，大多数研究都 尽管事实上许多医院感染都是致命的，但重点关注高毒力和细胞毒性的耐甲氧西林金黄色葡萄球菌菌株 由MRSA分离株引起，在离体模型和正常小鼠中表现出低毒力。这项建议旨在 从功能上剖析了导致医院环境中死亡的宿主和细菌导向机制。的 这项探索性R21中提出的工作是新颖的，因为它利用了一种新的抗生素医院小鼠模型 条件反射，我们发现它降低了感染的屏障，就像住院病人一样。利用这个模型， 我们将研究在健康小鼠中无毒的低细胞毒性菌株如何能够诱导 肺炎这项研究在技术上也是创新的，因为Dual RNA-seq将首次用于MRSA 感染的肺部，以确定病原体和宿主基因网络在医院感染的重要性。总之， 这项工作将极大地影响抗MRSA新治疗策略的发展， 可用于治疗益处的新的细菌因子，以及可用于治疗的宿主途径， 未来免疫疗法的目标。

PROJECT SUMMARY Pneumonia accounts for more deaths than any other infectious disease worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of hospital-acquired pneumonia. The prevalence of MRSA is increasing worldwide. To confront the growing problem of MRSA, we require a greater understanding of the host-pathogen interactions during infection. This remains poorly understood partly due to the lack of in vivo models relevant to infections occurring in healthcare settings. Most research to date has focused on highly virulent and cytotoxic MRSA strains, despite the fact that many nosocomial infections are caused by MRSA isolates that exhibit low virulence in ex vivo models and in normal mice. This proposal aims to functionally dissect host- and bacterial-directed mechanisms that lead to mortality in nosocomial settings. The work proposed in this exploratory R21 is novel as it utilizes a new nosocomial murine model of antibiotic conditioning, which we found lowers the barrier to infection, mimicking hospitalized patients. Using this model, we will investigate how low cytotoxic strains, which are avirulent in healthy mice, are capable of inducing pneumonia. This study is also technically innovative, as Dual RNA-seq will be utilized for the first time in MRSA infected lungs to identify pathogen and host gene-networks important during nosocomial infections. Altogether, the proposed work can greatly impact the development of new treatment strategies against MRSA by discovering novel bacterial factors which may be exploited for therapeutic benefit, as well as host pathways that could be targeted by future immunotherapies.