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.
13Bacterial virulence may rely on secondary metabolism, but core metabolism genes are assumed to be 14 necessary primarily for bacterial growth. To assess this assumption, we correlated the genome, the 15 transcriptome and the pathogenicity of 30 fully sequenced Pseudomonas strains using two Drosophila 16 and one mouse infection assay. In accordance with previous studies gene presence-absence does not 17 explain differences in virulence among P. aeruginosa strains, but merely between P. aeruginosa and 18 other Pseudomonas species. Similarly, classical gene expression analysis of highly vs. lowly pathogenic P. 19 aeruginosa strains identifies many virulence factors, and only a few metabolism genes related to 20 virulence. Nevertheless, assessing the virulence of 553 core metabolic and 95 random non-metabolic 21 gene mutants of P. aeruginosa PA14, we found 16.5% of the core metabolic and 8.5% of the non-22 metabolic genes to be necessary for full virulence. Strikingly, 11.8% of the core metabolism genes 23 exhibit defects in virulence that cannot be attributed to auxotrophy. The compromised in virulence 24 metabolic gene mutants were mapped in multiple pathways and exhibited further defects in acute 25 virulence phenotypes and in a mouse lung infection model. Functional transcriptomics re-analysis of 26 core metabolism at the pathway level, reveals amino-acid, succinate, citramalate, and chorismate 27 biosynthesis and beta-oxidation as important for full virulence and expression of these pathways 28 indicative of virulence in various strains. Thus, P. aeruginosa virulence variation, which to this point 29 remains unpredictably combinatorial at the gene level, can be dissected at the pathway level via 30 combinatorial trancriptome and functional core metabolism analysis. 31 53 pathogens to a host-associated lifestyle 6, 16, 17 . 54 Besides the identification of many virulence factors and some of their immediate regulators, P.55 aeruginosa pathogenicity appears not to follow the same paths for each strain. P. aeruginosa strains can 56 evolve, nevertheless, in the lung of cystic fibrosis patients, and some strains, such as CF5, are only 57 weakly pathogenic in models of acute infection 8,14 . Despite extensive efforts to link gene content with 58 pathogenicity of P. aeruginosa, virulence cannot be explained by the presence or absence of single 59 virulence genes 3, 8 . Accordingly, P. aeruginosa pathogenicity has been characterized as context 60 dependent, that is, genes required for pathogenicity in one strain may not necessarily contribute to 61 virulence in other strains. We hypothesized that, if not gene presence, then gene expression of virulence 62 factors and their regulators should be able to explain differences in pathogenicity among Pseudomonas 63 strains.3 64In the current study, we compared 30 fully sequenced Pseudomonas genomes using large-scale 65 comparisons at the protein sequence level. Primarily we sought to identify differences in the presence 66 and absence of genes that may explain t...
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