PT  - JOURNAL ARTICLE
AU  - Ruth Bowness
AU  - Mark A. J. Chaplain
AU  - Gibin G. Powathil
AU  - Stephen H. Gillespie
TI  - Modelling the effects of bacterial cell state and spatial location on tuberculosis treatment: Insights from a hybrid multiscale cellular automaton model
AID  - 10.1101/059113
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 059113
4099  - http://biorxiv.org/content/early/2016/08/17/059113.short
4100  - http://biorxiv.org/content/early/2016/08/17/059113.full
AB  - If improvements are to be made in tuberculosis (TB) treatment, an increased understanding of disease in the lung is needed. Studies have shown that bacteria in a less metabolically active state, associated with the presence of lipid bodies, are less susceptible to antibiotics, and recent results have highlighted the disparity in concentration of different compounds into lesions. Treatment success therefore depends critically on the responses of the individual bacteria that constitute the infection.We propose a hybrid, individual-based approach that analyses spatio-temporal dynamics at the cellular level, linking the behaviour of individual cells with the macroscopic behaviour of the microenvironment. The individual cells (bacteria, macrophages and T cells) are modelled using cellular automaton (CA) rules, and the evolution of oxygen, drugs and chemokine dynamics are incorporated in order to study the effects of the microenvironment in the pathological lesion. We allow bacteria to switch states depending on oxygen concentration, which affects how they respond to treatment. Using this multiscale model, we investigate the role of bacterial cell state and of initial bacterial location on treatment outcome. We demonstrate that when bacteria are located further away from blood vessels, and when the immune response is unable to contain the less metabolically active bacteria near the start of the simulations, a less favourable outcome is likely.