Abstract
Toxin-antitoxin (TA) systems in bacteria and archaea are small genetic elements consisting of the genes coding for an intracellular toxin and an antitoxin that can neutralize this toxin. In various cases, the toxins cleave the mRNA. In this theoretical work we use deterministic and stochastic modeling to explain how toxin-induced cleavage of mRNA in TA systems can lead to excitability, allowing large transient spikes in toxin levels to be triggered. By using a simplified network where secondary complex formation and transcriptional regulation are not included, we show that a two-dimensional, deterministic model captures the origin of such toxin excitations. Moreover, it allows to increase our understanding by examining the dynamics in the phase plane. By systematically comparing the deterministic results with Gillespie simulations we demonstrate that even though the real TA system is intrinsically stochastic, toxin excitations can be accurately described deterministically. A bifurcation analysis of the system shows that the excitable behavior is due to a nearby Hopf bifurcation in the parameter space, where the system becomes oscillatory. The influence of stress is modeled by varying the degradation rate of the antitoxin and the translation rate of the toxin. We find that stress increases the frequency of toxin excitations. The inclusion of secondary complex formation and transcriptional regulation does not fundamentally change the mechanism of toxin excitations. Finally, we show that including growth rate suppression and translational inhibition can lead to longer excitations, and even cause excitations in cases when the system would otherwise be non-excitable. To conclude, the deterministic model used in this work provides a simple and intuitive explanation of toxin excitations in TA systems.
Highlights
Toxin-antitoxin modules are small genetic elements, omnipresent on the genomes of bacteria and archaea, that code for a small intracellular toxin and its counteracting antitoxin [1,2,3]
Using stochastic Gillespie modeling, the authors have shown that the growth rate inhibition during stressful conditions may be linked to excitations in the free toxin level, which are only found in simulations if the cleavage of the mazEF mRNA itself is included in the model
For the model used in [19], we find that, for increased stress, toxin excitations are mainly present if the cleavage of mRNA by the toxins is included in the model (Fig 1D), suggesting that mRNA cleavage plays an essential role in triggering large spikes in the free toxin levels
Summary
Toxin-antitoxin modules are small genetic elements, omnipresent on the genomes of bacteria and archaea, that code for a small intracellular toxin and its counteracting antitoxin [1,2,3].
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