Abstract
The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose–response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose–response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose–response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen–host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose–response relationships with the underlying bistable dynamics of the model. Relying on in vitro experiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen–immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose–response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains of Listeria monocytogenes that should be examined.
Highlights
The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose–response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose–response model for listeriosis
While outbreaks due to L. monocytogenes are much less common as compared with those linked to Escherichia coli and Salmonella, their occurrence is associated with a high case fatality rate (20–30%) [1,2]
Owing to limited human data on this front, and the fact that mouse models have been widely used to study the immune response against L. monocytogenes because of the genetic and physiological similarities between a mouse and a human [18,45], we consider a study by Higginbotham et al who reported an in vitro experiment regarding the killing of L. monocytogenes by mouse macrophages [41]
Summary
L. monocytogenes travels along with food particles through the oesophagus and reaches the stomach within a few seconds (in this study, we disregard the effect of saliva in the mouth on the bacterial population). Stomach acid (HCl) is significant for a number of reasons It initiates protein digestion by activating pepsinogen that secretes from the gastric gland. Scientific experiments with rats [33], mice [34] and guinea pigs [6] showed that a significant portion of inoculated L. monocytogenes are killed following the first hours of ingestion. These data indicate that stomach fluid is a major deterrent for the survival and growth of L. monocytogenes. If the bacteria can manage to survive the stomach fluid and reach the small intestine, where the pH level is relatively neutral (6.4–7.4) [35], they may be able to replicate and grow
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