Modeling early events in Francisella tularensis pathogenesis

Abstract

Computational models can provide valuable insights into the mechanisms of infection and be used as investigative tools to support development of medical treatments. We develop a stochastic, within-host, computational model of the infection process in the BALB/c mouse, following inhalational exposure to Francisella tularensis SCHU S4. The model is mechanistic and governed by a small number of experimentally verifiable parameters. Given an initial dose, the model generates bacterial load profiles corresponding to those produced experimentally, with a doubling time of approximately 5 h during the first 48 h of infection. Analytical approximations for the mean number of bacteria in phagosomes and cytosols for the first 24 h post-infection are derived and used to verify the stochastic model. In our description of the dynamics of macrophage infection, the number of bacteria released per rupturing macrophage is a geometrically-distributed random variable. When combined with doubling time, this provides a distribution for the time taken for infected macrophages to rupture and release their intracellular bacteria. The mean and variance of these distributions are determined by model parameters with a precise biological interpretation, providing new mechanistic insights into the determinants of immune and bacterial kinetics. Insights into the dynamics of macrophage suppression and activation gained by the model can be used to explore the potential benefits of interventions that stimulate macrophage activation.

Macrophages use a bet-hedging strategy for antimicrobial activity in phagolysosomal acidification

“…During an infectious process when the immune system confronts numerous microbial cells, the random nature of the final phagosomal pH will result in some fraction of the infecting inoculum being controlled and possibly killed by initial ingestion, allowing antigen presentation. In this regard, the mean number of bacteria in the phagolysosomes and cytoplasm of macrophages infected with the intracellular pathogen Francisella tularensis exhibits stochastic dynamics (50), which in turn could result from the type of stochastic processes in phagolysosome formation noted here. Hence, chance in phagolysosomal pH acidification provides phagocytic cells with a mechanism to hedge their bets such that the stochastic nature of the process is itself a host defense mechanism.…”

Human Dose–Response Data for Francisella tularensis and a Dose‐ and Time‐Dependent Mathematical Model of Early‐Phase Fever Associated with Tularemia After Inhalation Exposure

“…The statistical characterization of the complete data set from 118 volunteers (112 febrile with measured IP, fever rise time, and near‐maximum fever) fills gaps in knowledge about early‐phase human tularemia unappreciated in previously published studies from portions of these data (Egan, Hall, & Leach, ; Jones, Nicas, Hubbard, Sylvester, & Reingold, ; Wood, Egan, & Hall, ). The statistical characterization of three parameters defining human fever profile are useful for comparisons to outputs of theoretical models of tularemia mechanisms, particularly IPs in animal models (Gillard, Laws, Lythe, & Molina‐París, ; Huang & Haas, ; Wood et al., ) and from human epidemiologic investigation (Egan et al., ). All of these studies considered F. tularensis strain Schu S4.…”

“…Gillard et al. () described theoretical mechanisms for tularemia progression in BALB/c mice administered 100 CFU by aerosol or nasopharyngeal routes for the first 48 hours of pathogenesis. Knowledge of the nature and magnitude of mechanisms driving pathogenesis in humans, nonhuman primates, and murine species would be needed for interspecies extrapolation of such modeling results in human health risk assessments.…”

B Lymphocyte as a Target of Bacterial Infections

“…Francisella-infected macrophages promote a systemic anti-inflammatory reaction with high levels of TGF-β [125], with fatal consequences for the infected individual [126]. The first studies that highlighted the involvement of B lymphocytes in F. tularensis infection date back to the late 1990s, where it was found that B cells rather than antibodies were critical for protection against this bacterium [127].…”