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Polymicrobial interactions between co-infecting cystic fibrosis pathogens

共感染囊性纤维化病原体之间的多种微生物相互作用

基本信息

批准号：
10026395
负责人：
Tiffany Zarrella
金额：
--
依托单位：
NATIONAL CANCER INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10026395
关键词：
Address Affect Antibiotic Resistance Bacteria Bacterial Infections Biochemical Cause of Death Cell Separation Cell Wall Cells Chronic Communication Communities Complex Cystic Fibrosis Disease Disease Outcome Environment Flow Cytometry Fractionation Genes Genetic Genetic Transcription Growth Heavy Metals Human Microbiome Infection Investigation Iron Lead Libraries Life Longitudinal Studies Lung infections Mass Spectrum Analysis Microbe Molecular Nature Nutrient Oxidation-Reduction Oxygen Pathogenesis Pathway interactions Phenazines Play Production Pseudomonas aeruginosa Quinolones Regulation Regulatory Pathway Reporter Research Research Personnel Respiratory System Respiratory Tract Infections Respiratory physiology Role Sampling Severity of illness Signal Pathway Signal Transduction Signaling Molecule Sputum Staphylococcus aureus Stimulus Stress Systems Biology Training Translating Work antimicrobial chronic infection co-infection colonization resistance combat cystic fibrosis infection cystic fibrosis patients emerging adult insight intercellular communication interest methicillin resistant Staphylococcus aureus microorganism mutant novel pathogen pathogenic bacteria promoter quorum sensing response screening therapeutic development transcriptome sequencing transposon sequencing trend

项目摘要

ABSTRACT In nature, microorganisms are typically found in multispecies communities, however most species are studied in isolation. Polymicrobial interactions in infections affect pathogenesis by influencing nutrient availability, colonization, and antibiotic resistance. In cystic fibrosis, a disease which is plagued by persistent respiratory infections, the interactions of the bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus affect disease severity. It is common for bacteria to sense other microbes and respond antagonistically within multispecies communities. Since P. aeruginosa frequently resides in multispecies environments and has the capacity to secrete a plethora of antimicrobials, this proposal aims to investigate such a sensing and response phenomenon between P. aeruginosa and S. aureus. It was recently discovered by our lab that P. aeruginosa senses molecules released by S. aureus, and subsequently responds by producing antimicrobials that are active against S. aureus, independent of the previously described bacterial cell wall sensing by P. aeruginosa. The proposed research will take a multi-dimensional approach to analyze the polymicrobial interactions between these co-infecting pathogens. To identify the specific S. aureus exoproducts that P. aeruginosa senses, an array of promoter-reporters will be employed to determine active molecules by fractionating S. aureus supernatant and using mass spectrometry, as well as by screening a S. aureus transposon library. The antimicrobial response by P. aeruginosa will be characterized by global transcriptional analysis using RNA-seq. Further, regulation of signaling cascades will be elucidated by Tn-seq, illuminating which genes are essential to antimicrobial production. The known and novel antimicrobials induced by this interspecies sensing will be determined by biochemical fractionation, identification of the active fractions with antimicrobial activity, and mass spectrometry. Due to a surge in antibiotic resistance in both P. aeruginosa and S. aureus, and the effect of these two pathogens on cystic fibrosis disease outcomes, it is imperative to elucidate the interactions between these co-infecting pathogens. This work will yield new insight into interbacterial communication, and reveal the molecular mechanisms governing antimicrobial production pathways that could be novel targets for the development of therapeutics for chronic bacterial infections.

摘要在自然界中，微生物通常存在于多物种群落中，但大多数物种都被研究与世隔绝感染中的多微生物相互作用通过影响营养物质的可利用性来影响发病机制，定植和抗生素耐药性。在囊性纤维化中，这种疾病受到持续呼吸道疾病的困扰感染，细菌病原体铜绿假单胞菌和金黄色葡萄球菌的相互作用影响疾病的严重程度。细菌通常会感知到其他微生物，并在体内产生对抗性反应。多物种群落由于铜绿假单胞菌经常居住在多物种环境中，分泌过多的抗菌剂的能力，该提案旨在研究这种感知和反应铜绿假单胞菌与S.金黄色。我们实验室最近发现铜绿假单胞菌感觉到S.金黄色葡萄球菌，并随后通过产生抗微生物剂，对S.金黄色葡萄球菌，独立于先前描述的由铜绿假单胞菌的细菌细胞壁感测。该研究将采用多维方法来分析多微生物相互作用在这些共同感染的病原体之间。为了确定具体的S。金黄色葡萄球菌外分泌产物，感测，启动子-报告子阵列将用于通过分级分离S来确定活性分子。金黄色葡萄球菌上清液和使用质谱，以及通过筛选S. aureus转座子文库。的铜绿假单胞菌的抗微生物应答将通过使用RNA-seq的全局转录分析来表征。此外，Tn-seq将阐明信号级联的调节，阐明哪些基因是必需的，抗菌剂生产。这种种间感应诱导的已知和新型抗菌药物将被通过生物化学分级分离测定，鉴定具有抗微生物活性的活性级分，和质谱分析法来由于铜绿假单胞菌和沙门氏菌的抗生素耐药性激增，金黄色葡萄球菌，这两种病原体对囊性纤维化疾病结局的影响，在这些共同感染的病原体之间。这项工作将对细菌间的通讯产生新的见解，揭示了控制抗菌剂生产途径的分子机制，这些途径可能成为新的靶点，慢性细菌感染疗法的发展。