Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

被引:263
作者
Rotem, Eitan [1 ,2 ]
Loinger, Adiel [1 ]
Ronin, Irine [1 ,2 ,3 ]
Levin-Reisman, Irit [1 ,2 ]
Gabay, Chana [1 ]
Shoresh, Noam [4 ]
Biham, Ofer [1 ]
Balaban, Nathalie Q. [1 ,2 ,3 ]
机构
[1] Hebrew Univ Jerusalem, Racah Inst Phys, IL-91904 Jerusalem, Israel
[2] Hebrew Univ Jerusalem, Ctr Nanosci & Nanotechnol, IL-91904 Jerusalem, Israel
[3] Hebrew Univ Jerusalem, Sudarsky Ctr Computat Biol, IL-91904 Jerusalem, Israel
[4] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA 02142 USA
基金
以色列科学基金会;
关键词
single-cell; stochasticity; systems biology; ESCHERICHIA-COLI; FLUCTUATING ENVIRONMENTS; MULTIDRUG TOLERANCE; GENE-EXPRESSION; SINGLE-CELL; NOISE; HIPA; NETWORKS; SYSTEMS; STRESS;
D O I
10.1073/pnas.1004333107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
In the face of antibiotics, bacterial populations avoid extinction by harboring a subpopulation of dormant cells that are largely drug insensitive. This phenomenon, termed "persistence," is a major obstacle for the treatment of a number of infectious diseases. The mechanism that generates both actively growing as well as dormant cells within a genetically identical population is unknown. We present a detailed study of the toxin-antitoxin module implicated in antibiotic persistence of Escherichia coli. We find that bacterial cells become dormant if the toxin level is higher than a threshold, and that the amount by which the threshold is exceeded determines the duration of dormancy. Fluctuations in toxin levels above and below the threshold result in coexistence of dormant and growing cells. We conclude that toxin-antitoxin modules in general represent a mixed network motif that can serve to produce a subpopulation of dormant cells and to supply a mechanism for regulating the frequency and duration of growth arrest. Toxin-antitoxin modules thus provide a natural molecular design for implementing a bet-hedging strategy.
引用
收藏
页码:12541 / 12546
页数:6
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