A Novel Stochastic Multi-Scale Model of Francisella tularensis Infection to Predict Risk of Infection in a Laboratory.

Jonathan Carruthers,Grant Lythe,Joseph J Gillard,Martín López-García,Carmen Molina-París,Thomas R Laws

doi:10.3389/fmicb.2018.01165

Jonathan Carruthers, Grant Lythe + Show 4 more

Open Access

https://doi.org/10.3389/fmicb.2018.01165

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Abstract

We present a multi-scale model of the within-phagocyte, within-host and population-level infection dynamics of Francisella tularensis, which extends the mechanistic one proposed by Wood et al. (2014). Our multi-scale model incorporates key aspects of the interaction between host phagocytes and extracellular bacteria, accounts for inter-phagocyte variability in the number of bacteria released upon phagocyte rupture, and allows one to compute the probability of response, and mean time until response, of an infected individual as a function of the initial infection dose. A Bayesian approach is applied to parameterize both the within-phagocyte and within-host models using infection data. Finally, we show how dose response probabilities at the individual level can be used to estimate the airborne propagation of Francisella tularensis in indoor settings (such as a microbiology laboratory) at the population level, by means of a deterministic zonal ventilation model.

Highlights

Francisella tularensis is a gram-negative, facultative bacteria and the causative agent of tularemia (Oyston et al, 2004; Oyston, 2008)
We show how the log-normally distributed rupture time estimated by Wood et al (2014) from experimental data (Lindemann et al, 2011), can be incorporated into this model, while maintaining the Markovian nature of the underlying stochastic process, and how first-step arguments allow one to compute the probability distribution of the total number of bacteria released by an infected phagocyte upon rupture
In order to compare with results by Wood et al (2014), let us note that the approach they use involves evaluating a deterministic logistic growth process at the median time taken for an infected phagocyte to rupture

Summary

Introduction

Francisella tularensis is a gram-negative, facultative bacteria and the causative agent of tularemia (Oyston et al, 2004; Oyston, 2008). Due to its high infectivity and ability to cause a debilitating disease with the inhalation of as few as 10 organisms, F. tularensis has been classified as a category A bioterrorism agent by the Centers for Disease Control and Prevention (CDC). F. tularensis can resist killing in the cytosol from reactive oxygen species (ROS) and can subsequently undergo multiple rounds of division within the host cell. Following this intracellular bacterial replication, the host phagocyte ruptures and dies, releasing its bacterial load back into the extracellular environment (Cowley and Elkins, 2011). It is important to understand how an individual may react to the infection, and when they develop tularemia

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