Investigating the relationship between antibiotics and nosocomial pneumonia.

调查抗生素与院内肺炎的关系。

• 批准号: 10078595
• 负责人: Victor J. Torres
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078595
• 关键词: Animals; Antibiotic Resistance; Antibiotics; Biological; Cessation of life; Clinical; Communicable Diseases; Communities; Community-Acquired Infections; Complement; Data; Development; Disease; Exhibits; Exposure to; Flow Cytometry; Future; Gene Expression Profile; Genes; Goals; Hospitals; Human; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Individual; Infection; Intoxication; Knock-out; Knowledge; Lead; Leucocidin; Lung; Lung infections; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Nosocomial Infections; Nosocomial pneumonia; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Pneumonia; Predisposition; Prevalence; Prevention; Process; Production; Research; Risk; Staphylococcus aureus; Staphylococcus aureus infection; Testing; Therapeutic; Time; Toxin; Vaccines; Virulence; Virulence Factors; Virulent; Work; antimicrobial; cell type; combat; conditioning; cost; cytotoxic; cytotoxicity; design; experimental study; health care settings; in vivo; in vivo Model; innovation; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutrophil; novel; novel therapeutics; pathogen; prevent; transcriptome sequencing; treatment strategy; ventilator-associated pneumonia

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.

项目概要 肺炎造成的死亡人数比全球任何其他传染病都要多。耐甲氧西林 金黄色葡萄球菌 (MRSA) 是医院获得性肺炎的最常见原因之一。这 MRSA 的患病率在全球范围内不断增加。为了应对日益严重的 MRSA 问题，我们需要更大的努力 了解感染期间宿主与病原体的相互作用。这仍然知之甚少，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 重点关注高毒力和细胞毒性的 MRSA 菌株，尽管事实上许多医院感染是 由在离体模型和正常小鼠中表现出低毒力的 MRSA 分离株引起。该提案旨在 从功能上剖析导致医院环境中死亡的宿主和细菌导向机制。这 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医院小鼠抗生素模型 我们发现调节可以降低感染屏障，模仿住院患者。使用这个模型， 我们将研究对健康小鼠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具有创新性，因为双 RNA 测序将首次用于 MRSA 受感染的肺部识别病原体和宿主基因网络在医院感染期间很重要。共， 拟议的工作可以通过发现 MRSA 的新治疗策略的开发产生重大影响 可用于治疗效果的新细菌因子，以及可用于治疗的宿主途径 未来免疫疗法的目标。