A novel adaptation of aldolase regulates virulence in Streptococcus pyogenes

Regulation of virulence factor expression is critical for pathogenic microorganisms that must sense and adapt to a dynamic host environment; yet, the signal transduction pathways that enable this process are generally poorly understood. Here, we identify LacD. 1 as a global regulator of virulence factor expression in the versatile human pathogen, Streptococcus pyogenes. LacD. 1 is derived from a class I tagatose- 1,6-bisphosphate aldolase homologous to those involved in lactose and galactose metabolism in related prokaryotes. However, regulation of transcription by LacD. 1 is not dependent on this enzymatic activity or the canonical catabolite repression pathway, but likely does require substrate recognition. Our results suggest that LacD. 1 has been adapted as a metabolic sensor, and raise the possibility that regulation of gene expression by metabolic enzymes may be a novel mechanism by which Gram-positive bacteria, including S. pyogenes, coordinate multiple environmental cues, allowing essential transcription programs to be coupled with perceived nutritional status.