Lack, Cameron (2021) Modelling the interactions between Mycobacterium tuberculosis and innate alveolar macrophages. PhD thesis, University of Warwick.

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Abstract

Tuberculosis (TB) kills over one million people annually, ranking it the leading cause of death from a single infectious agent. Generally a pulmonary infection, the primary route of transmission for the disease is respiratory. After being deposited in the lungs, Mycobacterium tuberculosis (Mtb) are met by the host’s first line of defence: the alveolar macrophage. The early interaction between the macrophages and the bacteria set the stage for how the disease develops in the lungs. Understanding these dynamics is a crucial step in understanding the variety of host responses observed, ranging from early clearance, to latent infection, to active disease. This thesis explores the development of mathematical models of these early interactions, and identifies key mechanisms contributing to the proliferation of the bacteria.

A literature search was used to identify the current biological and mathematical understanding of the processes and interactions involved in Mtb infections. This was followed by the development of a range of iterative mathematical models. The models were parameterised using maximum likelihood methods on a rich data set, which tracks, at the individual cell level, the interactions between macrophages and bacteria. A mechanistic approach was used during the model development process, with a focus on balancing biological realism with mathematical complexity. Each iteration of the model developed and built upon the previous, which resulted in a robust model that was able to capture the dynamics of macrophages and bacteria over the 200 hours tracked in the experiments.

Using sensitivity analysis and a range of computational experiments, the mechanisms involved in the system were analysed to identify factors contributing to the proliferation of bacteria. Naturally, the bacteria growth rate was the most dominant. While investigating the methods of control available to the macrophages, it was shown that a small reduction to the intracellular growth rate for all macrophages results in a more beneficial outcome than complete inhibition of growth in only some macrophages. It was further demonstrated that an increase to the rate of phagocytosis has a beneficial effect, but only up to a point, after which it becomes detrimental.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QA Mathematics Q Science > QR Microbiology R Medicine > RC Internal medicine
Library of Congress Subject Headings (LCSH):	Tuberculosis -- Mathematical models, Tuberculosis -- Transmission -- Mathematical models, Mycobacterial diseases, Macrophages
Official Date:	March 2021
Dates:	Date Event March 2021 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Mathematics for Real-World Systems Centre for Doctoral Training
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Keeling, Matthew James ; Hall, Ian
Sponsors:	Engineering and Physical Sciences Research Council ; Medical Research Council (Great Britain)
Format of File:	pdf
Extent:	xxxiii, 218 leaves : illustrations
Language:	eng

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