Polymicrobial interactions in the respiratory tract

呼吸道中多种微生物的相互作用

• 批准号: 10347350
• 负责人: Jennifer Melinda Bomberger
• 金额: --
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347350
• 关键词: Air; Anabolism; Antiviral Response; Apical; Bacteria; Bacterial Infections; Cell physiology; Chronic; Coculture Techniques; Communities; Complex; Cystic Fibrosis; Data; Dioxygenases; Environment; Epithelial; Epithelial Cells; Essential Amino Acids; Exhibits; Genes; Goals; Growth; Health; Immune response; Immunologics; In Vitro; Infection; Innate Immune Response; Innate Immune System; Interferons; Kynurenine; Lead; Life; Light; Link; Liquid substance; Lung diseases; Mediating; Mediator of activation protein; Metabolism; Microbe; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Nutrient; Nutritional Immunity; Organism; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Population; Population Dynamics; Production; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Pyocyanine; Reporting; Respiratory Disease; Respiratory System; Respiratory Tract Infections; Respiratory syncytial virus; Role; Shapes; Signal Transduction; Staphylococcus aureus; Structure; Surface; System; Time; Tryptophan; Tryptophan 2,3 Dioxygenase; Viral; Virus; Virus Diseases; Work; airway epithelium; antimicrobial; chronic infection; co-infection; commensal bacteria; cystic fibrosis airway; cystic fibrosis airway epithelia; cystic fibrosis patients; design; differential expression; equilibration disorder; experience; host-associated microbial communities; in vivo; insight; lung colonization; microbial; microbial community; microorganism interaction; mortality; mouse model; novel; pathogen; pathogenic bacteria; persistent bacteria; prevent; pulmonary function; pulmonary function decline; respiratory; respiratory colonization; respiratory infection virus; respiratory microbiome; respiratory virus; response; targeted treatment

ABSTRACT Persistent polymicrobial respiratory infections in individuals with Cystic Fibrosis (CF) are a significant cause of morbidity and mortality. The airway epithelium provides the first line of defense against respiratory infections and is a critical component of the innate immune system, but the dysregulated immune response in the CF lung is ineffective at clearing pathogens. Bacterial pathogens can displace commensal CF lung microbes to establish chronic infections, and this decreased microbial diversity correlates with declining patient health. Progression of CF respiratory disease is also influenced by coinfection with respiratory viruses. Acquisition of Pseudomonas aeruginosa in CF patients correlates with seasonal respiratory virus infections, and CF patients experience increased severe exacerbations and declines in lung function during respiratory viral coinfection. In light of our recent report that P. aeruginosa biofilm growth in association with CF airway epithelial cells (AECs) is enhanced during coinfection with respiratory viruses, and mediated by innate antiviral signaling, we hypothesize that virus coinfection alters microbial community dynamics in the CF airways, disturbing the balance between bacterial populations. To investigate this hypothesis, we will evaluate the impact of virus infection and the innate antiviral response on mixed-species bacterial biofilms in a CF airway epithelial cell co-culture model and in vivo murine model. Preliminary data show virus co-infection allows P. aeruginosa to outcompete Staphylococcus aureus in polybacterial biofilms on CF AECs, and P. aeruginosa exhibits enhanced production of a key antimicrobial, pyocyanin, during virus co-infection. The host innate antiviral immune response, through induction of indoleamine 2,3-dioxygenase-1 (IDO1) activity and the tryptophan metabolite kynurenine, appear to regulate pyocyanin induction. These results suggest previously unexplored roles for the host innate immune response and immunometabolism in shaping microbial communities in the respiratory tract during virus co-infection. To this end, we will (1) evaluate virus-specific and innate antiviral mechanisms influencing bacterial populations during virus co-infection, (2) determine the antimicrobial mechanism(s) P. aeruginosa employs to outcompete S. aureus during viral co-infection, and (3) evaluate the role of the host kynurenine pathway in mediating bacterial competition during virus co-infection. These studies will provide a novel link between the host innate immune response and metabolic processes in the epithelium that impact the propensity of bacterial pathogens to persistently colonize the airways in CF. Our goal is to elucidate molecular mechanisms that govern viral-bacterial interactions and shape host-associated microbial communities in CF and thus, identify new targets that could delay acquisition and chronic bacterial colonization, or work in conjunction with existing therapies to eradicate P. aeruginosa persistence in end stage CF lung disease.

摘要 患有囊性纤维化（CF）的个体中的持续性多微生物呼吸道感染是导致肺纤维化的重要原因。 发病率和死亡率。气道上皮提供了抵抗呼吸道感染的第一道防线， 是先天免疫系统的关键组成部分，但CF肺中的免疫应答失调， 对清除病原体无效。细菌性病原体可以取代肺内CF肺微生物， 慢性感染，这种微生物多样性的减少与患者健康状况的下降有关。进展 CF呼吸道疾病也受到呼吸道病毒合并感染的影响。获得假单胞菌 CF患者中的铜绿假单胞菌与季节性呼吸道病毒感染相关， 呼吸道病毒合并感染期间严重急性加重和肺功能下降增加。根据我们 最近报道，与CF气道上皮细胞（AEC）相关的铜绿假单胞菌生物膜生长增强 在与呼吸道病毒共感染期间，并通过先天性抗病毒信号传导介导，我们假设病毒 合并感染改变了CF气道中的微生物群落动态，扰乱了细菌和呼吸道之间的平衡。 人口。为了研究这一假设，我们将评估病毒感染和先天性抗病毒药物的影响。 在CF气道上皮细胞共培养模型和体内鼠模型中对混合物种细菌生物膜的反应 模型初步数据显示，病毒共感染使铜绿假单胞菌在感染中胜过金黄色葡萄球菌。 CF AEC上的多细菌生物膜，并且铜绿假单胞菌表现出关键抗菌剂的生产增强， 绿脓菌素，在病毒共感染期间。宿主先天性抗病毒免疫应答，通过诱导 吲哚胺2，3-双加氧酶-1（IDO 1）活性和色氨酸代谢物犬尿氨酸似乎调节 绿脓菌素诱导这些结果提示了宿主先天性免疫应答以前未探索的作用 以及在病毒共感染期间形成呼吸道中微生物群落的免疫代谢。到 为此，我们将（1）评估影响细菌种群的病毒特异性和先天性抗病毒机制 在病毒共感染过程中，（2）确定铜绿假单胞菌竞争S. （3）评价宿主犬尿氨酸途径在介导细菌性金黄色葡萄球菌感染中的作用， 病毒共感染期间的竞争。这些研究将提供宿主先天免疫与宿主免疫之间的新联系。 反应和代谢过程，影响细菌病原体的倾向， 在CF中持续地定殖于气道。我们的目标是阐明控制病毒-细菌 相互作用，并在CF中塑造宿主相关的微生物群落，从而确定新的目标， 延迟获得和慢性细菌定植，或与现有疗法联合使用， P.终末期CF肺病中铜绿假单胞菌的持续存在。