Abstract
BackgroundBacteria have developed a repertoire of signalling mechanisms that enable adaptive responses to fluctuating environmental conditions. The formation of biofilm, for example, allows persisting in times of external stresses, e.g. induced by antibiotics or a lack of nutrients. Adhesive curli fibers, the major extracellular matrix components in Escherichia coli biofilms, exhibit heterogeneous expression in isogenic cells exposed to identical external conditions. The dynamical mechanisms underlying this heterogeneity remain poorly understood. In this work, we elucidate the potential role of post-translational bistability as a source for this heterogeneity.ResultsWe introduce a structured modelling workflow combining logical network topology analysis with time-continuous deterministic and stochastic modelling. The aim is to evaluate the topological structure of the underlying signalling network and to identify and analyse model parameterisations that satisfy observations from a set of genetic knockout experiments. Our work supports the hypothesis that the phenotypic heterogeneity of curli expression in biofilm cells is induced by bistable regulation at the post-translational level. Stochastic modelling suggests diverse noise-induced switching behaviours between the stable states, depending on the expression levels of the c-di-GMP-producing (diguanylate cyclases, DGCs) and -degrading (phosphodiesterases, PDEs) enzymes and reveals the quantitative difference in stable c-di-GMP levels between distinct phenotypes. The most dominant type of behaviour is characterised by a fast switching from curli-off to curli-on with a slow switching in the reverse direction and the second most dominant type is a long-term differentiation into curli-on or curli-off cells. This behaviour may implicate an intrinsic feature of the system allowing for a fast adaptive response (curli-on) versus a slow transition to the curli-off state, in line with experimental observations.ConclusionThe combination of logical and continuous modelling enables a thorough analysis of different determinants of bistable regulation, i.e. network topology and biochemical kinetics, and allows for an incorporation of experimental data from heterogeneous sources. Our approach yields a mechanistic explanation for the phenotypic heterogeneity of curli fiber expression. Furthermore, the presented work provides a detailed insight into the interactions between the multiple DGC- and PDE-type enzymes and the role of c-di-GMP in dynamical regulation of cellular decisions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0183-x) contains supplementary material, which is available to authorized users.
Highlights
Bacteria have developed a repertoire of signalling mechanisms that enable adaptive responses to fluctuating environmental conditions
Logical analysis: topology and parameters As a first analysis step, we tested the consistency of the candidate models, constructed in the “Methods” section, with the 15 constraints (Table S1 in Additional file 1, rows indicated with a bold index) derived from the experimental observations (Fig. 1a)
We first describe the essential features of the system resulting from common properties of the feasible models and afterwards we present the consequences for the continuous modelling step
Summary
Bacteria have developed a repertoire of signalling mechanisms that enable adaptive responses to fluctuating environmental conditions. For example, can outlast antibiotic stress by forming biofilm colonies [2], or they may produce bacteriocins when sensing nutrient competition [3] This form of acute adaptation is often encoded in the bacterial signal transduction network, which enables multiple stable states and may give rise to phenotypic heterogeneity [4,5,6]. While heterogeneous all-or-nothing expression of the curli protein CsgB in isogenic wild type cells under identical environmental conditions was shown in [10, 11], subsequent work [7] allowed to infer interactions of the molecular components of the underlying signalling network. The ability of the suggested network to produce bistable behaviour (curli on/off ) and the influence of individual molecular components on single-cell dynamics still remains to be elucidated
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