Letter | Published:

Stabilization of cooperative virulence by the expression of an avirulent phenotype

Nature volume 494, pages 353356 (21 February 2013) | Download Citation


Pathogens often infect hosts through collective actions: they secrete growth-promoting compounds or virulence factors, or evoke host reactions that fuel the colonization of the host. Such behaviours are vulnerable to the rise of mutants that benefit from the collective action without contributing to it; how these behaviours can be evolutionarily stable is not well understood1. We address this question using the intestinal pathogen Salmonella enterica serovar Typhimurium (hereafter termed S. typhimurium), which manipulates its host to induce inflammation, and thereby outcompetes the commensal microbiota2,3. Notably, the virulence factors needed for host manipulation are expressed in a bistable fashion, leading to a slow-growing subpopulation that expresses virulence genes, and a fast-growing subpopulation that is phenotypically avirulent4,5. Here we show that the expression of the genetically identical but phenotypically avirulent subpopulation is essential for the evolutionary stability of virulence in this pathogen. Using a combination of mathematical modelling, experimental evolution and competition experiments we found that within-host evolution leads to the emergence of mutants that are genetically avirulent and fast-growing. These mutants are defectors that exploit inflammation without contributing to it. In infection experiments initiated with wild-type S. typhimurium, defectors increase only slowly in frequency. In a genetically modified S. typhimurium strain in which the phenotypically avirulent subpopulation is reduced in size, defectors rise more rapidly, inflammation ceases prematurely, and S. typhimurium is quickly cleared from the gut. Our results establish that host manipulation by S. typhimurium is a cooperative trait that is vulnerable to the rise of avirulent defectors; the expression of a phenotypically avirulent subpopulation that grows as fast as defectors slows down this process, and thereby promotes the evolutionary stability of virulence. This points to a key role of bistable virulence gene expression in stabilizing cooperative virulence and may lead the way to new approaches for controlling pathogens.

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We thank E. Slack, R. Kümmerli, M. Sellin and L. Robert for comments on the manuscript, G. Paul for input on the modelling, and Hardt laboratory members for discussions. M.D. was supported in part by the Fondation pour la Recherche Médicale. M.A., R.R.R. and W.-D.H. were supported by grants from the Swiss National Science Foundation.

Author information


  1. Institute of Microbiology, ETH Zurich, Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland

    • Médéric Diard
    • , Lisa Maier
    • , Mitja N. P. Remus-Emsermann
    •  & Wolf-Dietrich Hardt
  2. Institute of Integrative Biology, ETH Zurich, Universitaetsstr. 16, 8092 Zurich, Switzerland

    • Victor Garcia
    •  & Roland R. Regoes
  3. Department of Environmental Systems Science, ETH Zurich, and Department of Environmental Microbiology Eawag, Ueberlandstr. 133PO Box 611, 8600 Duebendorf, Switzerland

    • Martin Ackermann


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M.D., V.G. and R.R.R. conceived and analysed the mathematical simulations. M.D., V.G. and R.R.R. wrote the theoretical part of the paper. M.D., W.-D.H., L.M. (Supplementary Figs 14 and 20), M.N.P.R.-E (Supplementary Fig. 8) and M.A. designed the experiments and analysed the data. M.D., W.-D.H. and M.A. wrote the paper. M.D. and L.M. (Supplementary Figs 14 and 20) performed the experiments.

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Roland R. Regoes or Martin Ackermann or Wolf-Dietrich Hardt.

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    Supplementary information

    This file contains Supplementary Text and Data, Supplementary Table 1, Supplementary Figures 1-20 and Supplementary References.

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