| Authors | Ramos-Sevillano, E., Ercoli, G., Guerra-Assunção, J.A., Betts, M., Partridge, F., Fernandes, V.E., Wall, E., Gordon, S.B., Ferreira, D.M., Heyderman, R. and Brown, J.S. |
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| Description | Previous virulence screens have indicated potential roles during Streptococcus pneumoniae infection for the one-carbon metabolism pathway component Fhs and proline synthesis mediated by ProABC. To define how these metabolic pathways affect S. pneumoniae virulence we have investigated phenotypes and transcription profiles of Δfhs and ΔproABC strain mutants. S. pneumoniae capsular serotype 6B BHN418 Δfhs and ΔproABC mutant strains were markedly reduced virulence in mouse models of systemic infection and pneumonia, but were still able to colonise the nasopharynx. Although the Δfhs and ΔproABC mutant strains grew normally in complete media, both mutant strains had markedly impaired growth in chemically defined medium, human serum and human CSF. The ΔproABC strain also had impaired growth under conditions of osmotic and oxidative stress. When transferred to the serotype 2 D39 S. pneumoniae strain background, the Δfhs mutation replicated the virulence and growth in serum phenotype of the BHN418 mutation. In contrast, the D39 ΔproABC mutant could cause septicaemia and grow in human serum, indicating the role of this genetic locus during virulence is strain-specific. In human sera the Δfhs and ΔproABC mutants both had major derangements in global gene transcription affecting multiple but different metabolic pathways, identifying the corresponding S. pneumoniae metabolic functions affected by these genes under infection-related conditions. Our data demonstrate an essential role for the S. pneumoniae one- carbon metabolism and a strain-conditional role for proline biosynthesis for growth in physiological fluids and therefore systemic infection, and further demonstrate the vital importance of bacterial metabolism for disease pathogenesis. |
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