Polymicrobial Interactions in the Respiratory Tract

呼吸道中多种微生物的相互作用

• 批准号: 10794794
• 负责人: Jennifer Melinda Bomberger
• 金额: $ 39.12万
• 依托单位: DARTMOUTH COLLEGE
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10794794
• 关键词: Polymicrobial; Interactions; Respiratory; Tract

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 囊性纤维化(CF)患者持续的多菌呼吸道感染是 发病率和死亡率。呼吸道上皮是抵御呼吸道感染的第一道防线， 是先天免疫系统的重要组成部分，但肺组织中失调的免疫反应是 清除病原体效果不佳。细菌病原体可以取代共生性肺间质纤维化微生物建立 慢性感染，这种微生物多样性减少与患者健康下降相关。进展情况 Cf呼吸道疾病也受到与呼吸道病毒混合感染的影响。假单胞菌的获取 慢性支气管炎患者的铜绿假单胞菌与季节性呼吸道病毒感染相关，而慢性支气管炎患者经历 在呼吸道病毒合并感染期间，严重加重和肺功能下降的增加。鉴于我们的 最近报道铜绿假单胞菌的生物膜生长与CF的呼吸道上皮细胞(AECs)相关 在与呼吸道病毒合并感染期间，并通过先天抗病毒信号的介导，我们假设病毒 混合感染改变了CF呼吸道的微生物群落动态，扰乱了细菌之间的平衡 人口。为了研究这一假说，我们将评估病毒感染和先天抗病毒药物的影响。 CF型呼吸道上皮细胞共培养模型及小鼠体内对混合细菌生物膜的反应 模特。初步数据显示，病毒混合感染使铜绿假单胞菌在竞争中超过金黄色葡萄球菌 CFAEC和铜绿假单胞菌上的多菌生物膜显示出一种关键抗菌剂的增强产生， 绿青素，在病毒共感染期间。宿主先天抗病毒免疫反应，通过诱导 吲哚胺2，3-双加氧酶-1(IDO1)活性和色氨酸代谢物犬尿氨酸似乎在调节 绿青素诱导。这些结果暗示了宿主先天免疫反应的未知作用。 以及在病毒合并感染期间塑造呼吸道微生物群落的免疫新陈代谢。至 为此，我们将(1)评估影响细菌种群的病毒特异性和先天抗病毒机制 在病毒共感染过程中，(2)确定铜绿假单胞菌的抗菌机制(S)。 以及(3)评估宿主犬尿氨酸途径在介导细菌感染中的作用 病毒共感染期间的竞争。这些研究将在宿主的先天免疫之间提供一种新的联系 上皮细胞的反应和代谢过程影响细菌病原体对 坚持不懈地在科罗拉多州定居。我们的目标是阐明控制病毒-细菌的分子机制。 相互作用并塑造CF中与宿主相关的微生物群落，从而确定新的靶标 延迟获取和慢性细菌定植，或与现有治疗方法协同工作以根除 铜绿假单胞菌在终末期慢性阻塞性肺疾病中的持久性。