Mol Microbiol. 2012 Jul;85(1):67-88. doi: 10.1111/j.1365-2958.2012.08090

CodY orchestrates the expression of virulence determinants in emetic Bacillus cereus by impacting key regulatory circuits.

Frenzel E, Doll V, Pauthner M, Lücking G, Scherer S, Ehling-Schulz M.

Institute of Functional Microbiology, Department of Pathobiology, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria Lehrstuhl für Mikrobielle Ökologie, Department für Grundlagen der Biowissenschaften, Technische Universität München, Weihenstephaner Berg 3, D-85354 Freising Weihenstephan, Germany Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, D-81675 München, Germany Abteilung Mikrobiologie, Zentralinstitut für Ernährungs- und Lebensmittelforschung ZIEL, Technische Universität München, D-85350 Freising Weihenstephan, Germany.

Abstract

Bacillus cereus causes gastrointestinal diseases and local and systemic infections elicited by the depsipeptide cereulide, enterotoxins, phospholipases, cytolysins and proteases. The PlcR-PapR quorum sensing system activates the expression of several virulence factors, whereas the Spo0A-AbrB regulatory circuit partially controls the plasmid-borne cereulide synthetase (ces) operon. Here, we show that CodY, a nutrient-responsive regulator of Gram-positive bacteria, has a profound effect on both regulatory systems, which have been assumed to operate independently of each other. Deletion of codY resulted in downregulation of virulence genes belonging to the PlcR regulon and a concomitant upregulation of the ces genes. CodY was found to be a repressor of the ces operon, but did not interact with the promoter regions of PlcR-dependent virulence genes in vitro, suggesting an indirect regulation of the latter. Furthermore, CodY binds to the promoter of the immune inhibitor cereus metalloprotease InhA1, demonstrating that CodY directly links B. metabolism to virulence. In vivo studies using a Galleria mellonella infection model, showed that the codY mutant was substantially attenuated, highlighting the importance of CodY as a key regulator of pathogenicity. Our results demonstrate that CodY profoundly modulates cereus, possibly controlling the development of the virulence of B. pathogenic traits in suitable host environments.