title: CodY orchestrates the expression of virulence determinants in emetic Bacillus cereus by impacting key regulatory circuits.
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 metalloprotease InhA1, demonstrating that CodY directly links B. cereus 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 the virulence of B. cereus, possibly controlling the development of pathogenic traits in suitable host environments.
authors.affiliation: Institute of Functional Microbiology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Elrike
authors.initials: E
authors.lastname: Frenzel
authors.forename: Viktoria
authors.initials: V
authors.lastname: Doll
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauthner
authors.forename: Genia
authors.initials: G
authors.lastname: Lücking
authors.forename: Siegfried
authors.initials: S
authors.lastname: Scherer
authors.forename: Monika
authors.initials: M
authors.lastname: Ehling-Schulz
mesh_terms: D000818:Animals; D001409:Bacillus cereus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D047630:Depsipeptides / Q000096:biosynthesis*; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D007915:Lepidoptera / Q000382:microbiology; D008666:Metalloendopeptidases / Q000378:metabolism; D009876:Operon; D018085:Regulon; D014774:Virulence / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D047630:Depsipeptides; C089294:cereulide; D008666:Metalloendopeptidases