Mathematical modelling of the agr operon in Staphylococcus aureus

Abstract

Staphylococcus aureus is a pathogenic bacterium that utilises quorum sensing (QS), a cell-to-cell signalling mechanism, to enhance its ability to cause disease. QS allows the bacteria to monitor their surroundings and the size of their population, and S. aureus makes use of this to regulate the production of virulence factors. Here we describe a mathematical model of this QS system and perform a detailed time-dependent asymptotic analysis in order to clarify the roles of the distinct interactions that make up the QS process, demonstrating which reactions dominate the behaviour of the system at various timepoints. We couple this analysis with numerical simulations and are thus able to gain insight into how a large population of S. aureus shifts from a relatively harmless state to a highly virulent one, focussing on the need for the three distinct phases which form the feedback loop of this particular QS system.

The putative influence of the agr operon upon survival mechanisms used by Clostridium acetobutylicum

“…In previous publications [16,19] we have described and investigated a model of the agr operon with a view to developing novel techniques for combating staphylococcal pathogenesis. For this study we adapt the dimensional model described in Figure 4 of [16].…”

“…For this study we adapt the dimensional model described in Figure 4 of [16]. To bring the model in line with the sporulation initiation module, the proportion of agr up-regulated cells and the mRNA concentration (P and M from [16]) are taken to be quasi-steady.…”

“…Previous modelling studies have suggested that feedback into the two-component system is the key to a fully effective quorum-sensing system [16], but, interestingly, these two feedback loops appear to be absent in C. acetobutylicum [17]. Comparisons with the staphylococcal agr system indicate that, depending upon the mechanism of interaction between the agr system and the sporulation-initiation network, the clostridial agr circuitry may (at least in part) be in place either to moderate the number of spores that are formed (in order for this number to reflect the urgency of the situation), or simply as an energy-saving strategy.…”

“…Existing models of the agr operon relate to this quorum-sensing system in S. aureus and its effect upon virulence-factor production [16,18,19]; to our knowledge no models of the agr operon exist in the context of the clostridial species. In a similar vein, models of sporulation in Gram-positive bacteria predominantly concern B. subtilis, with three in particular incorporating genetic regulation of the initiation network [9,20,21] using methods similar to those that we shall exploit here.…”

“…H extracellular acids We note that, after [16], intracellular AgrB and AgrD are assumed to be present in equal quantities.…”