Essential role of proline synthesis and the one-carbon metabolism pathways for systemic virulence of Streptococcus pneumoniae

Ramos-Sevillano, Elisa, Ercoli, Giuseppe, Betts, Modupeh, Guerra-Assunção, José Afonso, Iverson, Amy, Frank, Matthew, Partridge, Frederick, Lo, Stephanie W, Fernandes, Vitor E, Nasher, Fauzy, Wall, Emma, Wren, Brendan, Gordon, Stephen B, Ferreira, Daniela ORCID: https://orcid.org/0000-0002-0594-0902, Heyderman, Rob, Rosch, Jason and Brown, Jeremy S (2024) 'Essential role of proline synthesis and the one-carbon metabolism pathways for systemic virulence of Streptococcus pneumoniae'. mBio, e0175824. (In Press)

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Abstract

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 the phenotypes, transcription, and metabolic profiles of Δfhs and ΔproABC mutants. S. pneumoniae capsular serotype 6B BHN418 Δfhs and ΔproABC mutant strains had strongly reduced virulence in mouse sepsis and pneumonia models but could colonize the nasopharynx. Both mutant strains grew normally in complete media but had markedly impaired growth in chemically defined medium, human serum, and human cerebrospinal fluid. The BHN418 ΔproABC strain also had impaired growth under conditions of osmotic and oxidative stress. The virulence role of proABC was strain specific, as the D39 ΔproABC strain could still cause septicemia and grow in serum. Compared to culture in broth, in serum, the BHN418 Δfhs and ΔproABC strains showed considerable derangement in global gene transcription that affected multiple but different metabolic pathways for each mutant strain. Metabolic data suggested that Δfhs had an impaired stringent response, and when cultured in sera, BHN418 Δfhs and ΔproABC were under increased oxidative stress and had altered lipid profiles. Loss of proABC also affected carbohydrate metabolism and the accumulation of peptidoglycan synthesis precursors in the BHN418 but not the D39 background, linking this phenotype to the conditional virulence phenotype. These data identify the S. pneumoniae metabolic functions affected by S. pneumoniae one-carbon metabolism and proline biosynthesis, and the role of these genetic loci for establishing systemic infection.

Item Type:	Article
Subjects:	QU Biochemistry > QU 4 General works WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 210 Streptococcal infections (General or not elsewhere classified)
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1128/mbio.01758-24
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	06 Nov 2024 15:49
Last Modified:	06 Nov 2024 15:49
URI:	https://archive.lstmed.ac.uk/id/eprint/25543

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