Aspergillus fumigatus Inhibits Pseudomonas aeruginosa in Co-culture: Implications of a Mutually Antagonistic Relationship on Virulence and Inflammation in the CF Airway

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.

Interactions of Aspergillus fumigatus and Stenotrophomonas maltophilia in an in vitro Mixed Biofilm Model: Does the Strain Matter?

“…In alignment with the previous reports on P. aeruginosa and A. fumigatus ( Reece et al, 2018 ), we described a significant increased in larvae mortality rate when A. fumigatus and S. maltophilia were inoculated in the same time, except for S. maltophilia of genogroup 2. This effect is dependent on the S. maltophilia strain used in the combination.…”

“…Interestingly, the clinical strain Sm_6-1 originated from CF-patient is the most virulent strain in G. mellonella model and incurred high mortality, suggesting that these isolates could be more pathogenic. It might be interesting to inoculate 2 strains of S. maltophilia and A. fumigatus from the same CF patient to analyze their virulence in G. mellonella , as described recently for P. aeruginosa and A. fumigatus ( Reece et al, 2018 ). We probably would not have an increase in larvae mortality due to adaptation of these isolates to co-exist in the same environment.…”

Dynamics of Mono- and Dual-Species Biofilm Formation and Interactions Between Paracoccidioides brasiliensis and Candida albicans

“…(Singulani et al, 2018). More recently, G. mellonella has been used to evaluate co-infection between fungi (Alcazar-Fuoli et al, 2015) or fungus and bacteria (Kean et al, 2017;Rossoni et al, 2017;Reece et al, 2018;Sheehan et al, 2020). Furthermore, some results are similar to those found in mammal models (Sheehan et al, 2020).…”

The presence of Aspergillus fumigatus is associated with worse respiratory quality of life in cystic fibrosis

“…We investigated the interaction between Af and Pa given the evidence of Pa inhibition of Af growth and mutual antagonism of Af towards Pa in vitro [34][35][36][37][38]. Interestingly, epidemiologic data suggest Pa are associated with higher odds for concurrent and subsequent Aspergillus infection [ 39 ].…”