A dual-host regulatory hub integrating biofilm formation and innate immunity resistance.

Vector-borne pathogens must adapt to sharply distinct host environments, yet the regulatory logic that coordinates transitions between opposing host-specific programs remains poorly defined. Here, we identify a minimal regulatory module in the flea-borne pathogen Yersinia pestis that integrates vector transmission with resistance to mammalian innate immunity. Screening of flea-induced genes uncovered the regulator HdfR, which acts primarily through activation of maoP, encoding a nucleoid-associated protein. This HdfR-MaoP module promotes biofilm-dependent foregut blockage in the flea while coordinating baseline envelope adaptations that limit complement recognition and inducible responses that confer resistance to antimicrobial peptides under mammalian host-like conditions. Functional interchangeability of HdfR and MaoP homologs reveals evolutionary conservation of this regulatory logic, and pharmacological perturbation of the module sensitizes Y. pestis to antimicrobial peptides. Together, these findings define a parsimonious and evolutionarily conserved regulatory hub that orchestrates bacterial success across abrupt environmental transitions and exposes a tractable point of intervention.