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The Two-Component System 09 of Streptococcus pneumoniae Is Important for Metabolic Fitness and Resistance during Dissemination in the Host.

ABSTRACT: The two-component regulatory system 09 of Streptococcus pneumoniae has been shown to modulate resistance against oxidative stress as well as capsule expression. These data and the implication of TCS09 in cell wall integrity have been shown for serotype 2 strain D39. Other data have suggested strain-specific regulatory effects of TCS09. Contradictory data are known on the impact of TCS09 on virulence, but all have been explored using only the rr09-mutant. In this study, we have therefore deleted one or both components of the TCS09 (SP_0661 and SP_0662) in serotype 4 S. pneumoniae TIGR4. In vitro growth assays in chemically defined medium (CDM) using sucrose or lactose as a carbon source indicated a delayed growth of nonencapsulated tcs09-mutants, while encapsulated wild-type TIGR4 and tcs09-mutants have reduced growth in CDM with glucose. Using a set of antigen-specific antibodies, immunoblot analysis showed that only the pilus 1 backbone protein RrgB is significantly reduced in TIGR4ΔcpsΔhk09. Electron microscopy, adherence and phagocytosis assays showed no impact of TCS09 on the TIGR4 cell morphology and interaction with host cells. In contrast, in vivo infections and in particular competitive co-infection experiments demonstrated that TCS09 enhances robustness during dissemination in the host by maintaining bacterial fitness.

SUBMITTER: Hirschmann S

PROVIDER: S-EPMC8306541 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In gram-positive bacteria, the transcriptional regulator CcpA is at the core of catabolite control mechanisms. In the human pathogen Streptococcus pneumoniae, links between CcpA and virulence have been established, but its role as a master regulator in different nutritional environments remains to be elucidated. Thus, we performed whole-transcriptome and metabolic analyses of S. pneumoniae D39 and its isogenic ccpA mutant during growth on glucose or galactose, rapidly and slowly metabolized carbohydrates presumably encountered by the bacterium in different host niches. CcpA affected the expression of up to 19% of the genome covering multiple cellular processes, including virulence, regulatory networks and central metabolism. Its prevalent function as a repressor was observed on glucose, but unexpectedly also on galactose. Carbohydrate-dependent CcpA regulation was also observed, as for the tagatose 6-phosphate pathway genes, which were activated by galactose and repressed by glucose. Metabolite analyses revealed that two pathways for galactose catabolism are functionally active, despite repression of the Leloir genes by CcpA. Surprisingly, galactose-induced mixed-acid fermentation apparently required CcpA, since genes involved in this type of metabolism were mostly under CcpA-repression. These findings indicate that the role of CcpA extends beyond transcriptional regulation, which seemingly is overlaid by other regulatory mechanisms. In agreement, CcpA influenced the level of many intracellular metabolites potentially involved in metabolic regulation. Our data strengthen the view that a true understanding of cell physiology demands thorough analyses at different cellular levels. Moreover, integration of transcriptional and metabolic data uncovered a link between CcpA and the association of surface molecules (e.g. capsule) to the cell wall. Hence, CcpA may play a key role in mediating the interaction of S. pneumoniae with its host. Overall, our results support the hypothesis that S. pneumoniae optimizes basic metabolic processes, likely enhancing in vivo fitness, in a CcpA-mediated manner.

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The Two-Component System 09 of Streptococcus pneumoniae Is Important for Metabolic Fitness and Resistance during Dissemination in the Host.

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