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Graduate School of Biomedical Sciences

The Bree Aldridge Lab

Mycobacterial Virulence and Drug Tolerance

TB kills millions of people every year. Mycobacterium tuberculosis remains the second deadliest infectious agent in the world. Our research focuses on understanding how mycobacteria tolerate stress and perturb host cell biology to evade killing by antibiotic treatment and the host immune response. We integrate single-cell measurements and computational modeling to quantitatively describe stress tolerance and virulence mechanisms of mycobacteria. We aim to use this knowledge to engineer improved therapeutics for treating tuberculosis.

Using live cell microscopy and quantitative image analysis, we recently found (Aldridge et al, 2012) that mycobacteria exhibit an asymmetric growth pattern (Fig 1). This unusual growth pattern deterministically generates closely related cells with different growth properties and tolerance to drug treatment. We continue to use live-cell microscopy and computational modeling to quantify the relative contributions of key physiological properties of mycobacteria on the ability of different subpopulations to tolerate a diverse range of stressors (Richardson et al, 2016Logsdon et al, 2017).


Figure 1. Mycobacterium smegmatis cells pulse-labeled with a fluorescent (green) amine reactive dye, marking old cell wall material. The bright field image is pseudo-colored blue.

We use engineering approaches to tackle the complexity of drug regimen design (Cokol et al., 2017) and cellular behaviors during the course of infection and treatment. We believe that the behaviors of both host and bacterial cells are determined by a combination of many dynamic factors. We aim to measure these important factors and navigate cell complexity by utilizing novel computational modeling tools. Key to our approach is the use of phase diagrams (Aldridge et al, 2011) to visualize cell phenotype relative to multiple parameters. We use this quantitative and multidisciplinary methodology to elucidate the determinants cell state and fate in both host macrophages and mycobacteria. These approaches are generalizable and have application to a broad range of biological and disease systems.