Abstract
We study the pathogenesis of Francisella tularensis infection with an experimental mouse model, agent-based computation and mathematical analysis. Following inhalational exposure to Francisella tularensis SCHU S4, a small initial number of bacteria enter lung host cells and proliferate inside them, eventually destroying the host cell and releasing numerous copies that infect other cells. Our analysis of disease progression is based on a stochastic model of a population of infectious agents inside one host cell, extending the birth-and-death process by the occurrence of catastrophes: cell rupture events that affect all bacteria in a cell simultaneously. Closed expressions are obtained for the survival function of an infected cell, the number of bacteria released as a function of time after infection, and the total bacterial load. We compare our mathematical analysis with the results of agent-based computation and, making use of approximate Bayesian statistical inference, with experimental measurements carried out after murine aerosol infection with the virulent SCHU S4 strain of the bacterium Francisella tularensis, that infects alveolar macrophages. The posterior distribution of the rate of replication of intracellular bacteria is consistent with the estimate that the time between rounds of bacterial division is less than 6 hours in vivo.
Highlights
Francisella tularensis, the causative agent of tularemia, is extremely infectious and considered a biothreat agent [1,2,3]
In some cases, infected cells release new infectious agents continuously over their lifetime. In others, such as the Francisella tularensis bacterium studied here, they are released in a single burst that coincides with the cell’s death
We show how a stochastic model, the birth-and-death process with catastrophe, can be used to characterise infection in a single cell, thereby allowing us to account for burst events and quantify the kinetics of pathogenesis in the lung, the initial site of infection, as well as in other organs that the infection spreads to
Summary
Francisella tularensis, the causative agent of tularemia, is extremely infectious and considered a biothreat agent [1,2,3]. The bacteria enter alveolar macrophages [11,12,13,14,15,16], evading initial immune recognition and inflammatory response because of their atypical lipopolysaccharide [17]. They are able to escape from phagosomes in less than an hour and, as illustrated, begin multiple rounds of replication in the cytosol [18,19,20,21]. The eventual death of the host macrophage [22] returns bacteria to the extracellular environment, from where they can migrate to another organ, or again infect macrophages in the lung
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