An integrated experimental-computational approach for predicting virulence in New Zealand white rabbits and humans following inhalation exposure to Bacillus anthracis spores

Abstract

Inhalation of Bacillus anthracis spores can lead to an anthrax infection that can be fatal. Previously published mathematical models have extrapolated kinetic rates associated with bacterial growth in New Zealand White (NZW) rabbits to humans, but to date, actual measurements of the underlying processes associated with anthrax virulence between species have not been conducted. To address this knowledge gap, we have quantified species-specific rate constants associated with germination, proliferation, and immune cell inactivation of B . anthracis Sterne using an in vitro test platform that includes primary lung epithelial and immune cells. The generated data was then used to develop a physiologically based biokinetic model (PBBK) which quantitatively compares bacterial growth and mean time to death under lethal conditions in rabbits and humans. Simulations based upon our in vitro data and previously published in vivo data from rabbits indicate that disease progression is likely to be faster in humans than in NZW rabbits under comparable total deposited dose conditions. With the computational framework established, PBBK parameters can now be refined using experimental data for lethal B . anthracis strains (e.g. Ames) under identical conditions in future studies. The PBBK model can also be linked to existing aerosol dosimetry models that account for species-specific differences in aerosol deposition patterns to further improve the human health risk assessment of inhalation anthrax.

Nasal anatomy and sniffing in respiration and olfaction of wild and domestic animals

“…The inhalation dosimetry of anthrax was numerically analyzed by Kabilan et al (93), revealing that the deposition distribution was highly sensitive to local flows and aerosol size. An integrated experimental-computational approach was proposed by Hess et al (94), which involved the use of in vitro data from rabbits to construct a physiologically based biokinetic model (PBBK). This PBBK could be linked to an existing aerosol dosimetry model, enabling consideration of species-specific variability.…”

Invited review: human air-liquid-interface organotypic airway tissue models derived from primary tracheobronchial epithelial cells—overview and perspectives

“…A range of progenitor cell-targeted growth factors and co-factors as well as trace elements, protective antioxidants, and vitamins are supplemented in the basal proliferation medium to enhance the longevity of the primary large airway epithelial cells. ALI airway cultures generated using these Medium kits have been widely utilized in various areas of respiratory research (Tanaka et al 2018 ; Hess et al 2019 ; Xia et al 2020 ).…”

Ventilation Modulation and Nanoparticle Deposition in Respiratory and Olfactory Regions of Rabbit Nose

“…Kabilan et al [17] numerically studied the deposition of inhaled anthrax, whose deposition was highly dependent upon the local flow characteristics. More recently, Hess et al [18] put forward an integrated computational-experimental approach by using in vitro data in rabbits to develop a physiologically-based biokinetic (PBBK) model, which can be combined to existent dosimetry models to consider species-specific variability. However, no data on ultrafine particle deposition in rabbits has been reported up to date, either experimentally or computationally [16].…”