Host- and microbial-mediated mucin degradation differentially shape Pseudomonas aeruginosa physiology and gene
Sabrina J Arif1, Kayla M Hoffman1, Jeffrey M Flynn1
1Department of Microbiology & Immunology, University of Minnesota, Minneapolis, Minnesota, United States of America.
Abstract:
Pseudomonas aeruginosa is a hallmark pathogen of cystic fibrosis (CF) airway infections, capable of reaching high cell densities despite its limited ability to directly utilize mucin glycoproteins as a nutrient source. In the CF lung, however, P. aeruginosa may access preferred carbon sources (e.g., amino acids and short-chain fatty acids) through metabolic cross-feeding with co-colonizing mucin-degrading microbes. Although host-derived enzymes such as neutrophil elastase can also degrade mucins, the extent to which host-mediated mucin breakdown supports P. aeruginosa growth remains unclear. Thus, here we compared the nutritional impact of microbial versus host mucolytic activity on P. aeruginosa physiology. Analyses of CF sputum revealed patient-specific variability in mucin integrity that is shaped by both host and microbial factors. We demonstrate that mucin degradation by anaerobic bacteria through proteolysis, glycolysis, and fermentation, promotes robust P. aeruginosa growth, unlike mucin processed by neutrophil elastase alone. Targeted metabolomics identified acetate and propionate as key metabolites driving this cross-feeding, while transcriptomic and phenotypic analyses revealed that P. aeruginosa engages in diauxic growth on a broader set of mucin-derived substrates. Unexpectedly, cross-feeding with anaerobes triggered the induction of P. aeruginosa denitrification and fermentation pathways, suggesting redox remodeling despite being cultured under oxygen-replete conditions. Finally, the transcriptional profile of P. aeruginosa grown on anaerobe-conditioned mucins more closely resembled its in vivo gene expression, more so than when grown on intact or neutrophil-degraded mucins. Together, these findings provide new insight into the potential role of interspecies metabolic interactions in shaping pathogen physiology in the inflammatory, polymicrobial, and mucus-rich environment of the CF airways.
Insights
Microbial breakdown of mucins fuels Pseudomonas aeruginosa growth in cystic fibrosis (CF) airways, unlike host enzyme degradation. This cross-feeding supports P. aeruginosa adaptation and gene expression in the CF lung environment.
Area of Science:
- Microbiology
- Host-Pathogen Interactions
- Metabolic Biochemistry
Background:
- Pseudomonas aeruginosa is a key pathogen in cystic fibrosis (CF) airways, often found with mucin-degrading microbes.
- P. aeruginosa has limited ability to use mucins directly, relying on cross-feeding for preferred nutrients.
- The role of host-derived enzymes versus microbial activity in mucin breakdown for P. aeruginosa growth is not fully understood.
Purpose of the Study:
- To compare the nutritional impact of microbial versus host mucolytic activity on P. aeruginosa physiology.
- To investigate the metabolic cross-feeding interactions between P. aeruginosa and mucin-degrading microbes in the CF lung.
- To understand how mucin degradation influences P. aeruginosa gene expression and adaptation in vivo.
Main Methods:
- Analysis of cystic fibrosis (CF) sputum for mucin integrity and microbial/host factors.
- Culturing P. aeruginosa with mucins degraded by anaerobic bacteria versus neutrophil elastase.
- Targeted metabolomics to identify key cross-feeding metabolites.
- Transcriptomic and phenotypic analyses to assess P. aeruginosa physiological responses.
- Comparison of in vitro gene expression profiles with in vivo data.
Main Results:
- Mucin degradation by anaerobic bacteria significantly promotes P. aeruginosa growth, unlike degradation by neutrophil elastase alone.
- Acetate and propionate were identified as key metabolites driving microbial cross-feeding.
- P. aeruginosa exhibited diauxic growth on mucin-derived substrates and induced denitrification and fermentation pathways.
- Transcriptional profiles of P. aeruginosa grown on anaerobe-conditioned mucins more closely resembled in vivo gene expression.
Conclusions:
- Interspecies metabolic interactions, particularly microbial mucin degradation, are crucial for P. aeruginosa growth and adaptation in the CF lung.
- Cross-feeding with anaerobic bacteria provides essential nutrients and influences P. aeruginosa physiology, including gene expression.
- Findings highlight the complex interplay of host and microbial factors in shaping pathogen behavior within the CF airway environment.
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