Speaker
Description
Tuberculosis (TB) remains a major global health challenge, with nearly 10 million new cases annually and increasing drug resistance.
As part of the ERA4TB initiative, which aims to advance new treatment regimens, multiple research institutes collaborated to develop and characterise in vitro granuloma-like structures (GLSs), aggregates of human PBMCs that exhibit key features of tuberculosis granulomas \cite{Puissegur2004}.
While physiologically more relevant than standard cell line models, GLS experiments remain costly, and studying granuloma biology in vivo is challenging. Host-directed therapies, which target the host immune response rather than the pathogen directly, remain relatively underexplored and represent an area where GLS could provide valuable information.
Computational modelling can complement GLS experiments by reducing cost and providing mechanistic insight\cite{Michael2024}. We developed an agent-based model (ABM) of GLS dynamics using PhysiCell, a scalable and extensible platform for simulating multicellular systems \cite{Ghaffarizadeh2018}.
The model was calibrated using a multi-laboratory dataset comprising CFU time series obtained from drug-free and drug-treated conditions, together with quantitative measures of GLS size and number, the latter extracted from microscopy images, both via expert annotation and automated machine learning analysis.
Given the inherent biological variability, this parameter estimation was performed using Approximate Bayesian Computation (ABC), yielding a posterior distribution for a subset of parameters~\cite{Tavar1997}.
Bibliography
@article{Puissegur2004,
title = {An in vitro dual model of mycobacterial granulomas to investigate the molecular interactions between mycobacteria and human host cells},
volume = {6},
ISSN = {1462-5822},
url = {http://dx.doi.org/10.1111/j.1462-5822.2004.00371.x},
DOI = {10.1111/j.1462-5822.2004.00371.x},
number = {5},
journal = {Cellular Microbiology},
publisher = {Hindawi Limited},
author = {Puissegur, Marie-Pierre and Botanch, Catherine and Duteyrat, Jean-Luc and Delsol, Georges and Caratero, Claude and Altare, Frederic},
year = {2004},
month = may,
pages = {423–433}
}
@article{Michael2024,
title = {A framework for multi-scale intervention modeling: virtual cohorts, virtual clinical trials, and model-to-model comparisons},
volume = {3},
ISSN = {2674-0702},
url = {http://dx.doi.org/10.3389/fsysb.2023.1283341},
DOI = {10.3389/fsysb.2023.1283341},
journal = {Frontiers in Systems Biology},
publisher = {Frontiers Media SA},
author = {Michael, Christian T. and Almohri, Sayed Ahmad and Linderman, Jennifer J. and Kirschner, Denise E.},
year = {2024},
month = jan
}
@article{Ghaffarizadeh2018,
title = {PhysiCell: An open source physics-based cell simulator for 3-D multicellular systems},
volume = {14},
ISSN = {1553-7358},
url = {http://dx.doi.org/10.1371/journal.pcbi.1005991},
DOI = {10.1371/journal.pcbi.1005991},
number = {2},
journal = {PLOS Computational Biology},
publisher = {Public Library of Science (PLoS)},
author = {Ghaffarizadeh, Ahmadreza and Heiland, Randy and Friedman, Samuel H. and Mumenthaler, Shannon M. and Macklin, Paul},
editor = {Poisot, Timothée},
year = {2018},
month = feb,
pages = {e1005991}
}
@article{Tavar1997,
title = {Inferring Coalescence Times From DNA Sequence Data},
volume = {145},
ISSN = {1943-2631},
url = {http://dx.doi.org/10.1093/genetics/145.2.505},
DOI = {10.1093/genetics/145.2.505},
number = {2},
journal = {Genetics},
publisher = {Oxford University Press (OUP)},
author = {Tavaré, Simon and Balding, David J and Griffiths, R C and Donnelly, Peter},
year = {1997},
month = feb,
pages = {505–518}
}
