Pseudomonas aeruginosa core metabolism exerts a widespread growth-independent control on virulence

Abstract

To assess the role of core metabolism genes in bacterial virulence - independently of their effect on growth - we correlated the genome, the transcriptome and the pathogenicity in flies and mice of 30 fully sequenced Pseudomonas strains. Gene presence correlates robustly with pathogenicity differences among all Pseudomonas species, but not among the P. aeruginosa strains. However, gene expression differences are evident between highly and lowly pathogenic P. aeruginosa strains in multiple virulence factors and a few metabolism genes. Moreover, 16.5%, a noticeable fraction of the core metabolism genes of P. aeruginosa strain PA14 (compared to 8.5% of the non-metabolic genes tested), appear necessary for full virulence when mutated. Most of these virulence-defective core metabolism mutants are compromised in at least one key virulence mechanism independently of auxotrophy. A pathway level analysis of PA14 core metabolism, uncovers beta-oxidation and the biosynthesis of amino-acids, succinate, citramalate, and chorismate to be important for full virulence. Strikingly, the relative expression among P. aeruginosa strains of genes belonging in these metabolic pathways is indicative of their pathogenicity. Thus, P. aeruginosa strain-to-strain virulence variation, remains largely obscure at the genome level, but can be dissected at the pathway level via functional transcriptomics of core metabolism.

Impact of Artificial Sputum Medium Formulation on Pseudomonas aeruginosa Secondary Metabolite Production

“…The low levels of total phenazines produced by PAO1 in Soothill ASM may reflect a shift of chorismate utilization away from phenazine biosynthesis toward the production of aromatic amino acids, as these amino acids are not present in the medium ( 37 ). The relatively low level of phenazines produced by PAO1 in Soothill ASM may reflect a reduced virulence phenotype, as highly virulent P. aeruginosa strains have upregulated transcription of genes related to chorismate biosynthesis ( 47 ). Phenazine production by PAO1 was highest in SCFM2 and SCFM3.…”

NtrBC Selectively Regulates Host-Pathogen Interactions, Virulence, and Ciprofloxacin Susceptibility of Pseudomonas aeruginosa

“…Although pathoadapted strains of P. aeruginosa isolated from chronic CF lung infections are characterized by reduced virulence overall, a recent study identified significant within-patient phenotypic diversity of isolates ( O’Brien et al., 2017 ) characterized by co-existence of strains that under-produce or overproduce pyoverdine and elastase. This might be caused by different availability of nutrients in niches of the lung, since virulence factor production is associated with core metabolic activity of P. aeruginosa ( Panayidou et al., 2020 ) and is inhibited following perturbation of metabolism during biofilm formation ( Perinbam et al., 2020 ). These observations align with what we observed herein.…”

Pseudomonas aeruginosa transcriptome adaptations from colonization to biofilm infection of skin wounds

“…P. aeruginosa (strain PAO1) gene expression during wound infection has also been compared with gene fitness (transposon insertion sequencing, Tn-Seq), finding that the essentiality of genes generally did not correlate with their changes in expression from minimal medium to wound infection, except for metabolic genes 15 . The expression of core metabolic genes has also been associated with virulence across P. aeruginosa strains 16 . Furthermore, the glyoxylate shunt impinges on virulence factor production 17 – 20 .…”