title: A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence.
abstract: Different biomolecules have been identified in bacterial pathogens that sense changes in temperature and trigger expression of virulence programs upon host entry. However, the dynamics and quantitative outcome of this response in individual cells of a population, and how this influences pathogenicity are unknown. Here, we address these questions using a thermosensing virulence regulator of an intestinal pathogen (RovA of Yersinia pseudotuberculosis) as a model. We reveal that this regulator is part of a novel thermoresponsive bistable switch, which leads to high- and low-invasive subpopulations within a narrow temperature range. The temperature range in which bistability is observed is defined by the degradation and synthesis rate of the regulator, and is further adjustable via a nutrient-responsive regulator. The thermoresponsive switch is also characterized by a hysteretic behavior in which activation and deactivation occurred on vastly different time scales. Mathematical modeling accurately mirrored the experimental behavior and predicted that the thermoresponsiveness of this sophisticated bistable switch is mainly determined by the thermo-triggered increase of RovA proteolysis. We further observed RovA ON and OFF subpopulations of Y. pseudotuberculosis in the Peyer's patches and caecum of infected mice, and that changes in the RovA ON/OFF cell ratio reduce tissue colonization and overall virulence. This points to a bet-hedging strategy in which the thermoresponsive bistable switch plays a key role in adapting the bacteria to the fluctuating conditions encountered as they pass through the host's intestinal epithelium and suggests novel strategies for the development of antimicrobial therapies.
authors.affiliation: Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Aaron Mischa
authors.initials: AM
authors.lastname: Nuss
authors.affiliation: Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schuster
authors.affiliation: Institute of Microbiology, Technical University Braunschweig, Braunschweig, Germany.
authors.forename: Louisa
authors.initials: L
authors.lastname: Roselius
authors.affiliation: Institute of Microbiology, Technical University Braunschweig, Braunschweig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Klein
authors.affiliation: Institute of Systems Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Bücker
authors.affiliation: Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Herbst
authors.affiliation: Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Ann Kathrin
authors.initials: AK
authors.lastname: Heroven
authors.affiliation: Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pisano
authors.affiliation: Institute of Systems Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wittmann
authors.affiliation: Institute of Microbiology, Technical University Braunschweig, Braunschweig, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Münch
authors.affiliation: Institute of Mathematics, Technical University Munich, Munich, Germany.|Institute of Computational Biology, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Microbiology, Technical University Braunschweig, Braunschweig, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Jahn
authors.affiliation: Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Petra
authors.identifier: http://orcid.org/0000-0001-8177-3280
authors.initials: P
authors.lastname: Dersch
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D013696:Temperature; D059008:Time-Lapse Imaging; D014157:Transcription Factors / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*; D015011:Yersinia pseudotuberculosis / Q000472:pathogenicity*; D015012:Yersinia pseudotuberculosis Infections / Q000469:parasitology*
chemical_list: D001426:Bacterial Proteins; C405626:RovA protein, Yersinia; D014157:Transcription Factors; D037521:Virulence Factors