Nontypeable Haemophilus influenzae infection impedes Pseduomonas aeruginosa colonization and persistence in mouse respiratory tract

Abstract

Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature wherein the predominant bacterial species changes as patients age. Young patients have populations dominated by pathobionts such as nontypeable Haemophilus influenzae (NTHi), that are eventually supplanted by pathogens such as Pseudomonas aeruginosa (Pa), which are more typical of late-stage CF disease. In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential infection of mice with NTHi followed by Pa showed significant reduction in Pa in the lungs as compared to infection with Pa alone. Coinfected mice also had reduced severity of airway tissue damage and lower levels of inflammatory cytokines as compared mice infected with Pa alone. Similar results were observed using heat-inactivated NTHi bacteria prior to Pa introduction. Based on these results, we conclude that NTHi can significantly reduce susceptibility to subsequent Pa infection, most likely due to immune priming rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF.