The Bordetella pertussis model of exquisite gene control by the global transcription factor BvgA

Bordetella pertussis causes whooping cough, an infectious disease that is reemerging despite widespread vaccination. A more complete understanding of B. pertussis pathogenic mechanisms will involve unravelling the regulation of its impressive arsenal of virulence factors. Here we review the action of the B. pertussis response regulator BvgA in the context of what is known about bacterial RNA polymerase and various modes of transcription activation. At most virulence gene promoters, multiple dimers of phosphorylated BvgA (BvgA~P) bind upstream of the core promoter sequence, using a combination of high- and low-affinity sites that fill through cooperativity. Activation by BvgA~P is typically mediated by a novel form of class I/II mechanisms, but two virulence genes, fim2 and fim3, which encode serologically distinct fimbrial subunits, are regulated using a previously unrecognized RNA polymerase/activator architecture. In addition, the fim genes undergo phase variation because of an extended cytosine (C) tract within the promoter sequences that is subject to slipped-strand mispairing during replication. These sophisticated systems of regulation demonstrate one aspect whereby B. pertussis, which is highly clonal and lacks the extensive genetic diversity observed in many other bacterial pathogens, has been highly successful as an obligate human pathogen.