Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity

Abstract

Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients' acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation.respiratory syncytial virus | nutritional immunity | cystic fibrosis | Pseudomonas aeruginosa | biofilm

Viral–bacterial interactions in the respiratory tract

“…Moreover, elevated temperature and extracellular ATP occurring during viral infection can trigger the release of pneumococci from biofilms and induce changes in the bacterial transcriptome, associated with improved bacterial stress responses, altered metabolism and increased virulence (Marks et al, 2013;Pettigrew et al, 2014). Viral infections differentially impact the formation and maintenance of P. aeruginosa biofilms: while the release of extracellular iron and transferrin stimulates biofilm formation after RSV infection, the release of hydrogen peroxide during HRV infection triggers the release of P. aeruginosa and facilitates transmigration of bacteria through the epithelial layer and might thus contribute to the dissemination of infection (Chattoraj et al, 2011b;Hendricks et al, 2016).…”

Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis

“…We have recently demonstrated that RSV, RV, and adenovirus infections and the resulting type I and III IFN responses enhance P. aeruginosa biofilm growth on CF AECs (18). Moreover, RSV infection promotes the release from CF AECs of the host iron-binding protein transferrin, which is required for RSV-mediated biofilm growth (18).…”

“…We have recently demonstrated that RSV, RV, and adenovirus infections and the resulting type I and III IFN responses enhance P. aeruginosa biofilm growth on CF AECs (18). Moreover, RSV infection promotes the release from CF AECs of the host iron-binding protein transferrin, which is required for RSV-mediated biofilm growth (18). Iron is a necessary nutrient for P. aeruginosa biofilm growth on AECs, and a strong positive correlation between increased airway iron and disease severity in the CF patient lung has been reported (19).…”

Virally-Induced, Intracellular Biofilms; Novel Findings in Molluscum Contagiosum

“…The intracellular microbes in a biofilm are doubly protected from the immune system and other disease modifying agents. Viruses have been shown to assist bacteria (filamentous phages and Pseudomonas) in biofilm production and to enhance biofilm growth (Pseudomonas and respiratory syncytial virus) via dysregulation of immunity from alteration of iron metabolism [9,10]. This may be a potential role for the Herpes simplex virus that has been found in the brains of Alzheimer's patients [11] namely assisting the spirochetes that are present there to create biofilms and activate the innate immune system [3].…”