A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence

PLoS Pathogens

Aaron Mischa Nuss¹  Ann Kathrin Heroven¹  Katharina Herbst¹  Fabio Pisano¹  Franziska Schuster¹  Dieter Jahn²  Johannes Müller³  Richard Münch⁴  Johannes Klein⁴  Louisa Roselius⁴  Petra Dersch⁴  Christoph Wittmann⁵  René Bücker⁵ 

[1] Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany;Institute of Computational Biology, Helmholtz Centre Munich, Neuherberg, Germany;Institute of Mathematics, Technical University Munich, Munich, Germany;Institute of Microbiology, Technical University Braunschweig, Braunschweig, Germany;Institute of Systems Biotechnology, Saarland University, Saarbrücken, Germany

关键词: Yersinia pseudotuberculosis;    Plasmid construction;    Fluorescence microscopy;    Flow cytometry;    Cell fusion;    Peyer's patches;    Gastrointestinal tract;    Yersinia;   

DOI  :  10.1371/journal.ppat.1006091

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY