A Multi-Serotype Approach Clarifies the Catabolite Control Protein A Regulon in the Major Human Pathogen Group A Streptococcus

• Published in: Scientific reports 2016-09, Vol.6 (1), p.32442-32442, Article 32442
• Main Authors: DebRoy, Sruti, Saldaña, Miguel, Travisany, Dante, Montano, Andrew, Galloway-Peña, Jessica, Horstmann, Nicola, Yao, Hui, González, Mauricio, Maass, Alejandro, Latorre, Mauricio, Shelburne, Samuel A.
• Format: Article
• Language: English
• Subjects: 631/1647/2217/2218; 631/326/421; Animal models; Animals; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Carbon sources; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Gram-positive bacteria; Humanities and Social Sciences; Humans; Inactivation; Mice; multidisciplinary; Nucleotide Motifs; Pathogens; Regulon; Repressor Proteins - genetics; Repressor Proteins - metabolism; Science; Serogroup; Serotypes; Streptococcal Infections - microbiology; Streptococcal Infections - mortality; Streptococcal Infections - pathology; Streptococcus; Streptococcus infections; Streptococcus pyogenes - classification; Streptococcus pyogenes - genetics; Streptococcus pyogenes - metabolism; Streptococcus pyogenes - pathogenicity; Survival Analysis; Transcriptome; Virulence
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep32442

Catabolite control protein A (CcpA) is a highly conserved, master regulator of carbon source utilization in gram-positive bacteria, but the CcpA regulon remains ill-defined. In this study we aimed to clarify the CcpA regulon by determining the impact of CcpA-inactivation on the virulence and transcriptome of three distinct serotypes of the major human pathogen Group A Streptococcus (GAS). CcpA-inactivation significantly decreased GAS virulence in a broad array of animal challenge models consistent with the idea that CcpA is critical to gram-positive bacterial pathogenesis. Via comparative transcriptomics, we established that the GAS CcpA core regulon is enriched for highly conserved CcpA binding motifs (i.e. cre sites). Conversely, strain-specific differences in the CcpA transcriptome seems to consist primarily of affected secondary networks. Refinement of cre site composition via analysis of the core regulon facilitated development of a modified cre consensus that shows promise for improved prediction of CcpA targets in other medically relevant gram-positive pathogens.