53 research outputs found
Positive feedback and noise activate the stringent response regulator Rel in mycobacteria
Phenotypic heterogeneity in an isogenic, microbial population enables a
subset of the population to persist under stress. In mycobacteria, stresses
like nutrient and oxygen deprivation activate the stress response pathway
involving the two-component system MprAB and the sigma factor, SigE. SigE in
turn activates the expression of the stringent response regulator, rel. The
enzyme polyphosphate kinase 1 (PPK1) regulates this pathway by synthesizing
polyphosphate required for the activation of MprB. The precise manner in which
only a subpopulation of bacterial cells develops persistence, remains unknown.
Rel is required for mycobacterial persistence. Here we show that the
distribution of rel expression levels in a growing population of mycobacteria
is bimodal with two distinct peaks corresponding to low (L) and high (H)
expression states, and further establish that a positive feedback loop
involving the mprAB operon along with stochastic gene expression are
responsible for the phenotypic heterogeneity. Combining single cell analysis by
flow cytometry with theoretical modeling, we observe that during growth,
noise-driven transitions take a subpopulation of cells from the L to the H
state within a "window of opportunity" in time preceding the stationary phase.
We find evidence of hysteresis in the expression of rel in response to changing
concentrations of PPK1. Our results provide, for the first time, evidence that
bistability and stochastic gene expression could be important for the
development of "heterogeneity with an advantage" in mycobacteria.Comment: Accepted for publication in PLoS On
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