A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence

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 pathogenicit...

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Main Authors:	Nuss, Aaron Mischa, Schuster, Franziska, Roselius, Louisa, Klein, Johannes, Bücker, René, Herbst, Katharina, Heroven, Ann Kathrin, Pisano, Fabio, Wittmann, Christoph, Münch, Richard, Müller, Johannes, Jahn, Dieter, Dersch, Petra
Format:	Online
Language:	English
Published:	Public Library of Science 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179001/

id	pubmed-5179001
recordtype	oai_dc
spelling	pubmed-51790012017-01-04 A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence Nuss, Aaron Mischa Schuster, Franziska Roselius, Louisa Klein, Johannes Bücker, René Herbst, Katharina Heroven, Ann Kathrin Pisano, Fabio Wittmann, Christoph Münch, Richard Müller, Johannes Jahn, Dieter Dersch, Petra Research Article 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. Public Library of Science 2016-12-22 /pmc/articles/PMC5179001/ /pubmed/28006011 http://dx.doi.org/10.1371/journal.ppat.1006091 Text en © 2016 Nuss et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Nuss, Aaron Mischa Schuster, Franziska Roselius, Louisa Klein, Johannes Bücker, René Herbst, Katharina Heroven, Ann Kathrin Pisano, Fabio Wittmann, Christoph Münch, Richard Müller, Johannes Jahn, Dieter Dersch, Petra
spellingShingle	Nuss, Aaron Mischa Schuster, Franziska Roselius, Louisa Klein, Johannes Bücker, René Herbst, Katharina Heroven, Ann Kathrin Pisano, Fabio Wittmann, Christoph Münch, Richard Müller, Johannes Jahn, Dieter Dersch, Petra A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence
author_facet	Nuss, Aaron Mischa Schuster, Franziska Roselius, Louisa Klein, Johannes Bücker, René Herbst, Katharina Heroven, Ann Kathrin Pisano, Fabio Wittmann, Christoph Münch, Richard Müller, Johannes Jahn, Dieter Dersch, Petra
author_sort	Nuss, Aaron Mischa
title	A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence
title_short	A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence
title_full	A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence
title_fullStr	A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence
title_full_unstemmed	A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence
title_sort	precise temperature-responsive bistable switch controlling yersinia virulence
description	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.
publisher	Public Library of Science
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179001/
_version_	1613812971618697216

A Precise Temperature-Responsive Bistable Switch Controlling Yersinia Virulence

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