Regulation of viral-bacterial co-infections by immunometabolism

SUMMARY/ABSTRACT Pseudomonas aeruginosa is a 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. CF patients show a reduced ability to clear P. aeruginosa acquired during respiratory viral infections and frequently new pseudomonal colonization in people with CF follows a respiratory viral infection. We have shown that virus co-infection, and the subsequent antiviral interferon response, promote biofilm conversion by P. aeruginosa. Interferon has potent antiviral activity, but in addition, interferon stimulated gene (ISG) effector functions have been reported to promote pathogen replication, suggesting that pathogens have evolved to subvert and even benefit from the interferon response. Decades of research demonstrate metabolic reprogramming as part of the host response to acute viral infections, with induction of aerobic glycolysis being a common observation. Our preliminary data suggest that the innate antiviral immune response through IFN signaling induces aerobic glycolysis during RSV infection, while still maintaining oxidative phosphorylation in the respiratory epithelium. Using an improved model to culture P. aeruginosa biofilms in association with human CF airway epithelial cells and a RSV mouse infection model, we will examine mechanisms by which antiviral interferon signaling promotes biofilm conversion by P. aeruginosa through a mechanism of metabolic reprogramming. To this end, we will determine how metabolic reprogramming of the respiratory epithelium facilitates viral-bacterial co-infection, define how secreted metabolic products from the virus-infected respiratory epithelium promote P. aeruginosa persistence and chronic infection by impairing antibacterial function in recruited macrophages and promoting bacterial biofilm growth. 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.