Viral-bacterial co-infections in the lung

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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.