Abstract
Clostridium botulinum produces botulinum neurotoxins (BoNTs), highly potent substances responsible for botulism. Currently, mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic information beyond group level but integrate many component processes, such as signalling, membrane permeability and metabolic activity. In this paper we present a scheme for modelling neurotoxin production in C. botulinum Group I type A1, based on the integration of diverse information coming from experimental results available in the literature. Experiments show that production of BoNTs depends on the growth-phase and is under the control of positive and negative regulatory elements at the intracellular level. Toxins are released as large protein complexes and are associated with non-toxic components. Here, we systematically review and integrate those regulatory elements previously described in the literature for C. botulinum Group I type A1 into a population dynamics model, to build the very first computational model of toxin production at the molecular level. We conduct a validation of our model against several items of published experimental data for different wild type and mutant strains of C. botulinum Group I type A1. The result of this process underscores the potential of mathematical modelling at the cellular level, as a means of creating opportunities in developing new strategies that could be used to prevent botulism; and potentially contribute to improved methods for the production of toxin that is used for therapeutics.
Highlights
Found in any soil or water environment, the spore forming Gram-positive rodshaped bacterium Clostridium botulinum and two other clostridia (C. baratii and C. butyricum) can, under suitable anaerobic conditions, release botulinum neurotoxins (BoNTs) [1,2]
Mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic
This study is primarily focused on the mathematical modelling of gene expression, toxin production and population growth that are observed in strains of C. botulinum Group I type A1
Summary
Found in any soil or water environment, the spore forming Gram-positive rodshaped bacterium Clostridium botulinum and two other clostridia (C. baratii and C. butyricum) can, under suitable anaerobic conditions, release botulinum neurotoxins (BoNTs) [1,2]. BoNTs cause botulism, a severe neuro-paralytic disease that can lead to death in humans as well as in a range of other mammals and birds [3,4]. There are fewer cases of foodborne illness caused by C. botulinum than by bacteria of the Salmonella genus, the death rate from botulism is relatively high, 17.3 percent, compared with 0.5 percent for Salmonella [12]. The severity of the disease and the widespread presence and persistence of C. botulinum spores make botulism a global health concern and a cause for vigilance [2]
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