A direct link between carbohydrate utilization and virulence in the major human pathogen group A Streptococcus.

Published

Journal Article

Although central to pathogenesis, the molecular mechanisms used by microbes to regulate virulence factor production in specific environments during host-pathogen interaction are poorly defined. Several recent ex vivo and in vivo studies have found that the level of group A Streptococcus (GAS) virulence factor gene transcripts is temporally related to altered expression of genes encoding carbohydrate utilization proteins. These findings stimulated us to analyze the role in pathogenesis of catabolite control protein A (CcpA), a GAS ortholog of a key global regulator of carbohydrate metabolism in Bacillus subtilis. Inasmuch as the genomewide effects of CcpA in a human pathogen are unknown, we analyzed the transcriptome of a DeltaccpA isogenic mutant strain grown in nutrient-rich medium. CcpA influences the transcript levels of many carbohydrate utilization genes and several well characterized GAS virulence factors, including the potent cytolysin streptolysin S. Compared with the wild-type parental strain, the DeltaccpA isogenic mutant strain was significantly less virulent in a mouse model of invasive infection. Moreover, the isogenic mutant strain was significantly impaired in ability to colonize the mouse oropharynx. When grown in human saliva, a nutrient-limited environment, CcpA influenced production of several key virulence factors not influenced during growth in nutrient-rich medium. Purified recombinant CcpA bound to the promoter region of the gene encoding streptolysin S. Our discovery that GAS virulence and complex carbohydrate utilization are directly linked through CcpA provides enhanced understanding of a mechanism used by a Gram-positive pathogen to modulate virulence factor production in specific environments.

Full Text

Duke Authors

Cited Authors

  • Shelburne, SA; Keith, D; Horstmann, N; Sumby, P; Davenport, MT; Graviss, EA; Brennan, RG; Musser, JM

Published Date

  • February 5, 2008

Published In

Volume / Issue

  • 105 / 5

Start / End Page

  • 1698 - 1703

PubMed ID

  • 18230719

Pubmed Central ID

  • 18230719

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.0711767105

Language

  • eng

Conference Location

  • United States