CcpA regulates central metabolism and virulence gene expression in Streptococcus mutans

Department of Oral Biology, University of Florida College of Dentistry, P.O. Box 100424, Gainesville, Fl. 32610, USA

^* To whom correspondence should be addressed. Email: rburne{at}dental.ufl.edu.

	Abstract

CcpA globally regulates transcription in response to carbohydrate availability in many Gram-positive bacteria, but its role in S. mutans remains enigmatic. Using the fructan hydrolase (fruA) gene of S. mutans as a model, we demonstrate that CcpA does indeed play a direct role in carbohydrate catabolite repression (CCR). Subsequently, the expression of 170 genes was shown to be differently expressed ( 2-fold) in glucose-grown wild-type (UA159) and CcpA-deficient (TW1) strains (p 0.001). However, only 96 genes showed altered expression between UA159 and TW1 in cells cultivated in the poorly-repressing substrate galactose. Interestingly, 90 genes were differently expressed in wild-type S. mutans when comparing glucose- or galactose-grown cells, but the expression of 515 genes was altered in the CcpA-deficient strain in a similar comparison. Overall, the results support a major role for CcpA in CCR and regulation of gene expression, but reveal that a substantial CcpA-independent network exists in S. mutans to regulate gene expression in response to carbohydrate source. Based on these genetic studies, biochemical and physiologic experiments demonstrated that loss of CcpA impacts the ability of S. mutans to transport and to grow on selected sugars. Also, the CcpA-deficient strain displayed an enhanced capacity to produce acid from intracellular stores of polysaccharides, could grow faster at pH 5.5, and could acidify the environment more rapidly and to a greater extent than the parental strain. Thus, CcpA directly modulates the pathogenic potential of S. mutans through global control of gene expression.