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Understanding how Mycobacterium Copes with Stress

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Bree Aldridge & Michelle Logsdon and a diagram of their experiment

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one-third of the world’s population and is the leading cause of death due to a single infectious agent. About 10% of cases progress into active infection and have a very high mortality rate (~50%) if left untreated. It is not known why certain patients progress to active disease. Host factors, such as immune deterioration due to HIV co-infection and aging are involved in re-activation but we have a poor understanding of the contribution of bacterial populations to infection progression. Certain macrophages are able to activate successful antimicrobial functions against Mtb while others fail in this regard and become a growth niche for intracellular Mtb.

Michelle Logsdon, a Molecular Microbiology PhD student working in the lab of Bree Aldridge is examining how subpopulations of Mtb persist in stressful environments and prevent clearance of infection. Dr. Aldridge showed previously that mycobacterial cells exhibit asymmetric growth and division patterns. Their innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Importantly, we have shown that differences in cell size at initiation of antibiotic treatment contribute to differential antibiotic susceptibility. These findings demonstrate a mechanism of generating bacterial diversity, allowing some cells to tolerate an antibiotic stress that easily kills others.

Asymmetric elongation and division in mycobacteria give rise to increased variability in cell size compared to model bacteria such as E. coli and B. subtilis, yet the distribution of this variability is stable over time. Size homeostasis is an important aspect of the physiology of all living cells because without a mechanism of regulation, cell sizes would rapidly diverge. Cell division dynamics leading to bacterial cell size control have been interpreted through mathematical models since the 1950s. These models are well studied in other bacteria, but not directly translatable given the physical asymmetry of mycobacteria.

Michelle is using live cell microscopy and fluorescent reporters to study the regulation of phenotypic heterogeneity in mycobacteria through the underlying coordination of growth, division, and cell cycle timing within single cells. She has collaborated with Harvard biophysicists Dr. Ariel Amir and Po-Yi Ho to develop a model of cell size control for the unusual asymmetric growth patterns of mycobacteria.  Historically, a major obstacle to improving TB therapies has been our poor understanding of the growth state of the Mtb bacterium during infection. Michelle's work characterizing regulation of cell cycle and division under controlled conditions prepares us to evaluate adaptions of these processes during infection. Identifying key adaptions that allow Mtb persistence within a host has the potential to streamline the search for new antibiotics against the world’s most deadly infection.