Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli
- KU Leuven - University of Leuven, Belgium
Abstract
While specific mutations allow organisms to adapt to stressful environments, most changes in an organism's DNA negatively impact fitness. The mutation rate is therefore strictly regulated and often considered a slowly-evolving parameter. In contrast, we demonstrate an unexpected flexibility in cellular mutation rates as a response to changes in selective pressure. We show that hypermutation independently evolves when different Escherichia coli cultures adapt to high ethanol stress. Furthermore, hypermutator states are transitory and repeatedly alternate with decreases in mutation rate. Specifically, population mutation rates rise when cells experience higher stress and decline again once cells are adapted. Interestingly, we identified cellular mortality as the major force driving the quick evolution of mutation rates. Together, these findings show how organisms balance robustness and evolvability and help explain the prevalence of hypermutation in various settings, ranging from emergence of antibiotic resistance in microbes to cancer relapses upon chemotherapy.
Data availability
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Highly ethanol tolerant Escherichia coli with hypermutation phenotypePublicly available at the NCBI SRA repository (Accession no: PRJNA344553).
Article and author information
Author details
Funding
Agentschap voor Innovatie door Wetenschap en Technologie (Strategic Basic Research Fellowship,121525)
- Toon Swings
Fonds Wetenschappelijk Onderzoek (Postdoctoral Fellowship,1249117N)
- Karin Voordeckers
Onderzoeksraad, KU Leuven (IDO/09/010)
- Kevin J Verstrepen
- Jan Michiels
Onderzoeksraad, KU Leuven (IDO/13/008)
- Jan Michiels
Onderzoeksraad, KU Leuven (CREA/13/019)
- Maarten Fauvart
Onderzoeksraad, KU Leuven (DBOF/12/035; DBOF/14/049)
- Kevin J Verstrepen
- Jan Michiels
Fonds Wetenschappelijk Onderzoek (KAN2014 1.5.222.14)
- Maarten Fauvart
Onderzoeksraad, KU Leuven (PF/10/010)
- Kevin J Verstrepen
- Jan Michiels
Interuniversity Attraction Poles-Belgian Science Policy Office (IAP P7/28)
- Jan Michiels
H2020 European Research Council (241426)
- Kevin J Verstrepen
Human Frontier Science Program (RGP0050/2013)
- Kevin J Verstrepen
Fonds Wetenschappelijk Onderzoek (G047112N)
- Jan Michiels
Vlaams Instituut voor Biotechnologie
- Kevin J Verstrepen
European Molecular Biology Organization
- Kevin J Verstrepen
Fonds Wetenschappelijk Onderzoek (Postdoctoral Fellowship,12O1917N)
- Bram Van den Bergh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Wenying Shou, Fred Hutchinson Cancer Research Center, United States
Version history
- Received: November 3, 2016
- Accepted: April 18, 2017
- Accepted Manuscript published: May 2, 2017 (version 1)
- Version of Record published: May 12, 2017 (version 2)
Copyright
© 2017, Swings et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli
eLife 6:e22939.
https://doi.org/10.7554/eLife.22939
Further reading
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- Microbiology and Infectious Disease
The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived ‘memory’ of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb−/−) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.
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- Medicine
- Microbiology and Infectious Disease
Background:
End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.
Methods:
The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.
Results:
Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.
Conclusions:
Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.
Funding:
F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.
