A dual-host regulatory hub integrating biofilm formation and innate immunity resistance
Abstract 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.
Authors
- Sébastien Janel (ORCID: https://orcid.org/0000-0001-6736-3162)
- Virginia S. Lioy (ORCID: https://orcid.org/0000-0002-5366-0462)
- Mélanie Hillion (ORCID: https://orcid.org/0000-0003-2973-6153)
- Xavier Thuru (ORCID: https://orcid.org/0000-0002-0998-4160)
- Catherine Robbe‐Masselot (ORCID: https://orcid.org/0000-0001-6266-6033)
- Julie Hardouin (ORCID: https://orcid.org/0000-0003-4588-9811)
- Charlotte Clarisse (ORCID: https://orcid.org/0000-0001-5767-7934)
- François Pierre (ORCID: https://orcid.org/0000-0002-7067-062X)
- Amélie Dewitte
- Florent Sebbane (ORCID: https://orcid.org/0000-0003-3811-9691)
- Mounia Kortebi
- Bontemps-Gallo Sébastien
- Alexandre Baillez
- Hassiba Bouafia (ORCID: https://orcid.org/0009-0003-0909-8585)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université de Lille (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Center for Infection and Immunity of Lille (FR)
- Normandie Université (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- Unité de Glycobiologie Structurale et Fonctionnelle (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- CEA Paris-Saclay (FR)
- Polymères, Biopolymères, Surfaces (FR)
- CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers (FR)
- Université de Rouen Normandie (FR)
- Institut National des Sciences Appliquées Rouen Normandie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-01
- DOI
- https://doi.org/10.1038/s41467-026-77307-4
- Primary Topic
- Yersinia bacterium, plague, ectoparasites research
- Type
- article
- Field-Weighted Citation Impact
- 0.00