Viral-bacterial co-infections in the lung

肺部病毒-细菌双重感染

• 批准号: 8903519
• 负责人: Jennifer Melinda Bomberger
• 金额: $ 37.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903519
• 关键词: Accounting; Acute; Address; Antibiotic Resistance; Antibiotic Therapy; Antiviral Agents; Apical; Bacteria; Biological Models; Chronic; Communities; Complex; Cystic Fibrosis; Data; Development; Epithelial Cells; Equilibrium; Genes; Goals; Grant; Growth; Health; Homeostasis; Human; Immune response; Immunity; Infection; Influenza; Integration Host Factors; Interferons; Iron; Label; Link; Lung; Membrane Microdomains; Microbe; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Multivesicular Body; Nutrient; Nutritional; Pathogenesis; Pathway interactions; Proteins; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Regulatory Pathway; Reporting; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Signal Transduction; Staging; Transferrin; Transferrin Receptor; Viral; Virus; Virus Activation; Virus Diseases; Work; airway epithelium; airway surface liquid; cystic fibrosis airway; cystic fibrosis patients; design; disease characteristic; extracellular; insight; microorganism interaction; mortality; new therapeutic target; novel; overexpression; pathogen; pathogenic bacteria; prevent; programs; protein transport; receptor; research study; respiratory; respiratory infection virus; respiratory virus; response; trafficking; transcytosis; viperin

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is the major respiratory pathogen in the pathogenesis of Cystic Fibrosis (CF) and the ineffective immune response to this pathogen is thought to cause the majority of the lung damage characteristic of this disease. In the later stages of CF, P. aeruginosa reside in biofilm communities in the lung, accounting for their resistance to antibiotic therapies. To date, little is known about host factors that promote the transition of P. aeruginosa from acute to chronic infection in CF. It has been reported that CF patients show a reduced ability to clear P. aeruginosa acquired during respiratory viral infections and 85% of new pseudomonal colonization in CF patients followed a respiratory viral infection within 3 weeks. We have demonstrated that virus co-infection, and the subsequent antiviral type III interferon response, promote biofilm conversion by P. aeruginosa. Type III interferon has potent antiviral activity, but in addition, interferon stimulated gene (ISG) effecto functions have been reported to promote pathogen replication, suggesting that pathogens have evolved to subvert and even benefit from the interferon response. A fundamental aspect in microbial interactions is the relentless battle for nutrients, including iron, where the host makes every effort to restrict access to pathogens and the pathogens have developed sophisticated strategies to acquire the nutrients they require for growth from the host. Using a unique model to culture P. aeruginosa biofilms in association with human CF airway epithelial cells, we will examine whether the host response to viral infection, namely type III interferon signaling, promotes biofilm conversion by P. aeruginosa through a mechanism of inappropriate iron secretion. To this end, we will (1) define the iron regulatory pathways that are altered by virus infection and type III interferon signaling in the airway epithelium, (2) define the mechanism by which iron is mobilized into the airway surface liquid and how P. aeruginosa acquires host iron and (3) define a role for the ISG, viperin, in promoting iron secretion from airway epithelial cell to enhance bacterial biofilm growth. The proposed experiments would provide a novel link between viral co-infection and the establishment of chronic bacterial colonization, with important implications in the progression of CF lung disease. Our goal is to elucidate the molecular mechanism for virus-stimulated bacterial biofilms and thus, identify new targets that could delay acquisition and chronic bacterial colonization, or work in conjunction with existing therapies, to eradicate P. aeruginosa in CF patients.

描述（由申请人提供）：铜绿假单胞菌是囊性纤维化（CF）发病机制中的主要呼吸道病原体，并且对该病原体的无效免疫反应被认为是导致该疾病的大部分肺损伤特征的原因。在 CF 的后期阶段，铜绿假单胞菌驻留在肺部的生物膜群落中，这就是它们对抗生素治疗产生耐药性的原因。迄今为止，对于促进 CF 中铜绿假单胞菌从急性感染转变为慢性感染的宿主因素知之甚少。据报道，CF 患者清除呼吸道病毒感染期间获得的铜绿假单胞菌的能力下降，并且 CF 患者中 85% 的新假单胞菌定植发生在呼吸道病毒感染后 3 周内。我们已经证明，病毒共感染以及随后的抗病毒 III 型干扰素反应可促进铜绿假单胞菌的生物膜转化。 III 型干扰素具有有效的抗病毒活性，但此外，据报道，干扰素刺激基因 (ISG) 效应功能可促进病原体复制，这表明病原体已经进化到颠覆甚至受益于干扰素反应。微生物相互作用的一个基本方面是对营养物质（包括铁）的不懈争夺，宿主在其中制造 尽一切努力限制病原体的接触，而病原体已经制定了复杂的策略，从宿主那里获取生长所需的营养。使用独特的模型来培养与人 CF 气道上皮细胞相关的铜绿假单胞菌生物膜，我们将检查宿主对病毒感染的反应，即 III 型干扰素信号传导，是否通过不适当的铁分泌机制促进铜绿假单胞菌生物膜转化。为此，我们将 (1) 定义因病毒感染和气道上皮中的 III 型干扰素信号传导而改变的铁调节途径，(2) 定义铁被调动到气道表面液体的机制以及铜绿假单胞菌如何获取宿主铁，以及 (3) 定义 ISG、蝰蛇蛋白在促进气道上皮细胞铁分泌以增强细菌的作用中的作用 生物膜生长。拟议的实验将提供病毒共感染和慢性细菌定植建立之间的新联系，对 CF 肺病的进展具有重要意义。我们的目标是阐明病毒刺激的细菌生物膜的分子机制，从而确定可以延迟获得和慢性细菌定植的新靶标，或与现有疗法结合使用，以根除 CF 患者中的铜绿假单胞菌。