Abstract
Many cystic fibrosis (CF) airway infections are considered to be polymicrobial and microbe–microbe interactions may play an important role in disease pathology. Pseudomonas aeruginosa and Aspergillus fumigatus are the most prevalent bacterial and fungal pathogens isolated from the CF airway, respectively. We have previously shown that patients co-colonized with these pathogens had comparable outcomes to those chronically colonized with P. aeruginosa. Our objective was to examine the interactions between A. fumigatus and P. aeruginosa, specifically the effects of co-colonization on biofilm formation, virulence and host pro-inflammatory responses. Our findings suggest that co-infections of A. fumigatus and P. aeruginosa in the Galleria mellonella acute infection model showed that pre-exposure of larvae to sub-lethal inocula of A. fumigatus increased the mortality caused by subsequent P. aeruginosa infection. Co-infection of human bronchial epithelial cells (CFBE41o-) with both pathogens did not enhance IL-6 and IL-8 production beyond the levels observed following single infections. In addition, both pathogens stimulated cytokine secretion via the same two mitogen-activated protein kinases (MAPKs) signaling pathways, ERK and p38. Mixed species biofilms showed overall reduced biofilm development with crystal violet staining. Quantification by species-specific qPCR revealed that both pathogens had mutually antagonistic effects on each other. A. fumigatus supernatants showed strong anti-Pseudomonal activity and gliotoxin was the main active agent. Gliotoxin resulted in varying levels of anti-biofilm activity toward other bacteria commonly found in the CF airways. Gliotoxin produced by A. fumigatus colonizing the CF airways may have a significant impact on the CF airway microbiome composition with potential clinical implications.
Highlights
Cystic fibrosis (CF) is the most common inherited life-shortening condition, characterized by mutations in the CF transmembrane conductance regulator (CFTR) gene
We have recently shown that 3.1% of Irish CF patients registered with the CF registry of Ireland were intermittently co-colonized with A. fumigatus and P. aeruginosa (Reece et al, 2017)
P. aeruginosa and A. fumigatus are isolated together from the sputum of CF patients and it has been well established that P. aeruginosa inhibits A. fumigatus in vitro (Kerr et al, 1999; Mowat et al, 2010; Ferreira et al, 2015; Shirazi et al, 2016; Anand et al, 2017) In contrast, much less is known about the impact of A. fumigatus on P. aeruginosa
Summary
Cystic fibrosis (CF) is the most common inherited life-shortening condition, characterized by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF airway disease is characterized by a continuous cycle of persistent infection and inflammation contributing to morbidity and mortality in CF. Detection and eradication of these infections remains a major challenge in CF lung disease management. P. aeruginosa is the leading cause of infection in patients with CF with approximately 28.4% being colonized by 71 months (Douglas et al, 2009). Intervention is paramount as P. aeruginosa is very difficult to eradicate once it has colonized the airways. P. aeruginosa is independently linked to worsened prognosis for CF patients; they have a decreased life expectancy of 30 years, compared with 40 years in non-colonized patients, experiencing a more rapid decline in pulmonary function with more frequent hospitalizations (Kosorok et al, 2001; Li et al, 2005). P. aeruginosa is a very accomplished bacterium and can adapt to life in the CF airway (Friman et al, 2013; Cullen and McClean, 2015)
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