Socio-evolutionary aspects of persistence
Persistence is a prime example of a ‘bet-hedging strategy’: an insurance policy for the population to survive exposure to lethal stresses such as bactericidal antibiotic treatment. Persistence has been observed in virtually every bacterial species in which it was investigated. However, specific quantitative features vary wildly among genera, species and even strains, raising the question why a particular bacterial strain has evolved to adopt a particular persister fraction as part of its survival strategy.
By combining wet-lab experiments, such as experimental evolution and competition assays, with mathematical modelling, we try to explain these quantitative aspects of persistence within a socio-evolutionary framework. In natural populations, persister levels are much lower than predicted using current theoretical models. Recently, we discovered that increased persistence is traded off against a lengthened lag phase as well as reduced stationary phase survival in Pseudomonas aeruginosa (Stepanyan et al., 2014).
These previously unknown pleiotropic costs of persistence can improve future models of persistence, facilitating the rational design of alternative therapeutic strategies for treating infectious diseases.
A defining feature of bet-hedging is that the size of the variant subpopulation should be tuned to the frequency of environmental change. However, this long-standing theoretical prediction is poorly supported by experimental evidence. In the case of persistence, the number of persisters is expected to reflect the frequency of antibiotic treatments.
Indeed, we recently discovered that persistence is a highly evolvable trait, and the evolved persister level strongly correlates with the frequency of antibiotic treatment (Van den Bergh et al., 2016), providing strong experimental support to classic bet-hedging theories. Moreover, evolution of high-persistence also occurs in the notorious ‘ESKAPE bugs’, a highly problematic group of nosocomial pathogens, indicating that these observations are also relevant in a clinical context (Michiels et al., 2016).
Indeed, persistence could represent a major component of the evolutionary response to antibiotics that is currently largely ignored in clinical settings.
Figure 1. Left. When populations are periodically exposed to amikacin every 1–10 days, persister levels evolve in correlation with the antibiotic treatment frequency. Inset: comparison of observed persister levels with theoretical persister levels based on a model in which only the switching rate a evolved (continuous line) or a model with additional pleiotropic effects (dashed line). Right. ESKAPE pathogens evolve rapidly towards high persister levels during intermittent aminoglycoside therapy.
Michiels J.E., Van den Bergh B., Verstraeten N., Fauvart M., Michiels J. (2016) In vitro emergence of high persistence upon periodic aminoglycoside challenge in the ESKAPE pathogens. Antimicrob. Agents Chemother. doi: 10.1128/AAC.00757-16 -- PubMed
Van den Bergh B., Michiels J.E., Wenseleers T., Windels E.M., Vanden Boer P., Kestemont D., De Meester L., Verstrepen K.J., Verstraeten N., Fauvart M. & Michiels J. (2016) Frequency of antibiotic application drives rapid evolutionary adaptation of Escherichia coli persistence. Nat. Microbiol. 1:16020 -- PubMed -- PDF
Stepanyan K., Wenseleers T., Duenez-Guzman E.A., Muratori F., Van den Bergh B., Verstraeten N., De Meester L., Verstrepen K.J., Fauvart M., Michiels J. (2015) Fitness trade-offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa. Mol. Ecol. 24:1572-1583 -- PubMed -- PDF
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