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.

Public Health Relevance

Individuals with Cystic Fibrosis (CF) develop chronic bacterial infections that result in declining lung function. These infections are polymicrobial, with multiple species of bacteria persistently colonizing the lungs. Colonization with commensal bacteria and increased bacterial diversity in the CF airways are associated with better patient outcomes. However, over time pathogens can outcompete beneficial species to establish chronic infections, leading to increased morbidity and mortality. Progression of CF lung disease is also influenced by frequent respiratory virus infections, which lead to increases in severe exacerbations. It is not well understood how viruses, bacteria, and the innate immune response to these infections interact to influence microbial community structure. We propose to study how the host immune response to a viral infection shifts the microbial dynamics in the CF respiratory tract to help us develop targeted therapies to prevent and treat chronic polymicrobial infections in the CF airways.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Lachowicz-Scroggins, Marrah Elizabeth
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University of Pittsburgh
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United States
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