Interaction between Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis

Abstract

Background: Cystic fibrosis (CF) is a disease characterized by chronic airway infection with a high incidence and poor prognosis. Pseudomonas aeruginosa and Aspergillus fumigatus are pathogens commonly found in CF patients. Clinically, these two microorganisms often coexist in the airway of CF patients. Combined infection with P. aeruginosa and A. fumigatus results in worsening lung function and clinical condition.

Methods: In this review, we focus on the mutual inhibition and promotion mechanisms of P. aeruginosa and A. fumigatus in CF patients. We also summarized the mechanisms of the interaction between these pathogenic microorganisms.

Results: P. aeruginosa inhibits A. fumigatus growth through the effects of phenazines, the quorum sensing system, iron competition, bacteriophages, and small colony variants. P. aeruginosa induces A. fumigatus growth through volatile organic compounds and subbacteriostatic concentrations of phenazines. A. fumigatus interferes with P. aeruginosa, affecting its metabolic growth via phenazine metabolic transformation, gliotoxin production, and reduced antibiotic sensitivity.

Discussion: Coexistence of P. aeruginosa and A. fumigatus can lead to both mutual inhibition and promotion. In different stages of CF disease, the interaction between these two pathogenic microorganisms may shift between promotion and inhibition. A discussion of the mechanisms of P. aeruginosa and A. fumigatus interaction can be beneficial for further treatment of CF patients and for improving the prognosis of the disease.

Keywords: Aspergillus fumigatus; Cystic fibrosis; Infection; Intermicrobial interaction; Pseudomonas aeruginosa.

Figure 1. Model for the interaction between P. aeruginosa and A. fumigatus.

Arrows indicate promotion. Arrows without heads indicate inhibition. Blue lines indicate the effect of P. aeruginosa on A. fumigatus. Red lines indicate the effect of A. fumigatus on P. aeruginosa. Pathway ① indicates the effect of P. aeruginosa on A. fumigatus by phenazine. PYO, PCA, PCN, and 1-HP inhibit A. fumigatus growth by inducing the production of ROS and RNS. Sub-MIC PYO, PCA, PCN, and 1-HP promote A. fumigatus growth by iron absorption. A. fumigatus growth can be inhibited by diRhls, which blocks β1,3 GS activity. Pathway ② shows the effect of A. fumigatus on P. aeruginosa by phenazine transformation. The metabolic conversion of phenazine by A. fumigatus inhibits the reduction of Fe³⁺ and affects QS system regulation in P. aeruginosa. Pathway ③ depicts the inhibition of toxic products and small molecules regulated by the QS system. The QS system in P. aeruginosa inhibits A. fumigatus growth via the effect of diRhls, PQS, and 3-oxo-C12 HSL. Pathway ④ shows that P. aeruginosa inhibits A. fumigatus growth via the effect of pyoverdine, Pf4, and SVSs on A. fumigatus iron deprivation. Pathway ⑤ and Pathway ⑥ illustrate P. aeruginosa promotion of A. fumigatus growth through the inhibition of host immune components and emission of VOCs. Pathway ⑦ shows that gliotoxin produced by A. fumigatus interferes with the metabolic growth of P. aeruginosa. Pathway ⑧ shows that A. fumigatus reduces the sensitivity of P. aeruginosa to antibiotics and promotes chronic infection.

Figure 2. Model for the interaction between P. aeruginosa and A. fumigatus by iron uptake and competition.

Pyoverdine and Pf4 phage bind to Fe³⁺ and promote uptake by P. aeruginosa. Pyoverdine and Pf4 phage deprive A. fumigatus of Fe³⁺ and inhibit its growth (pathway ①). Phenazine reduces Fe³⁺ to Fe²⁺ and promotes P. aeruginosa uptake of Fe²⁺. Phenazine is converted by A. fumigatus into metabolic products with potentially modified redox potentials. These products may inhibit the reduction of Fe³⁺ in P. aeruginosa (pathway ②). Sub-MIC PYO, PCN, and PCA reduce Fe³⁺ to Fe²⁺ and promote the FetCp/FtrA complex of A. fumigatus to take up Fe²⁺ (pathway ③). Sub-MIC 1-HP reduces Fe³⁺ to Fe²⁺, and two 1-HP molecules bind the newly formed Fe²⁺. This chelating activity induces iron starvation and activates triacetylfusarinine C (TAFC). TAFC promotes A. fumigatus uptake of Fe³⁺ and stimulates its growth (pathway ④).