Architecture and regulatory functions of c-di-GMP signaling in classical <i>Bordetella</i> species

Cyclic di-GMP (c-di-GMP) is a highly conserved bacterial second messenger that regulates important processes such as motility, biofilm formation and virulence. In this review, we investigate the architecture and regulatory functions of c-di-GMP signaling in classical Bordetella species, including B. bronchiseptica, B. parapertussis and B. pertussis. We examine how the c-di-GMP signaling pathway interacts with the BvgAS two-component system and other signaling pathways to coordinate virulence gene expression and surface-associated behaviors in these respiratory pathogens. In particular, we highlight the functions of characterized diguanylate cyclases (DGCs), phosphodiesterases (PDEs) and dual-domain proteins, focusing on regulatory modules such as the BdcA-DdpA scaffold complex, the oxygen-sensing DGC BpeGReg and the LapD-LapG proteolytic switch that controls BrtA adhesin. We also propose a model for the function of BvgR, a PDE-like protein lacking catalytic residues, and discuss how c-di-GMP suppresses the type III secretion system. Importantly, we highlight the diversity of the c-di-GMP network in classical Bordetella species, likely reflecting their evolutionary specialization. To conclude, we outline important open questions and suggest future research directions, including the identification of sensory ligands and c-di-GMP effectors. Overall, our review illustrates the importance of c-di-GMP as a critical, but still incompletely understood, regulatory hub in Bordetella pathogenesis.