Unveiling the Mechanisms of Phenotypic Heterogeneity in M. tuberculosis

The only single-celled organism ever found to sustain a steady growth rate throughout its life cycle is the rod-shaped tuberculosis (TB) bacterium, which the World Health Organization has once again named the leading infectious disease killer worldwide.

Researchers from Tufts University School of Medicine published their findings in the journal Nature Microbiology. They challenge fundamental theories of bacterial cell biology and provide insight into why the deadly pathogen so easily evades human immune system and medications.

The most basic thing you can study in bacteria is how they grow and divide, yet our study reveals that the TB pathogen is playing by a completely different set of rules compared to easier-to-study model organisms.”

Bree Aldridge, Professor and Study Co-Senior Author, School of Medicine, Tufts University

Bree Aldridge is also a Professor of Biomedical Engineering at the School of Engineering. He worked along with Ariel Amir of the Weizmann Institute of Science.

Certain aspects of the infection can rapidly change within their host and TB bacteria can thrive in people. This enables these outliers to evade identification or withstand therapy. Curing TB requires months of taking different drugs, and even then, only 85% of patients respond well to this treatment.

Aldridge and her colleagues speculate that the creation of more potent medicines has been impeded by gaps in the knowledge of the fundamental biology behind this occurrence.

However, obtaining answers turned out to be a laborious and tedious process. One of the first authors of the research, Christin (Eun Seon) Chung, a Postdoctoral Fellow at the School of Medicine, observed the activity of individual TB cells for three years in a facility designed to handle high-risk diseases.

Aldridge's team had to create and implement novel microscopy techniques to film the bacteria over weeks because TB bacteria double every around 24 hours, as opposed to 20 minutes for other model bacterial species, because TB bacteria are infamously small and prone to moving around, automatic analysis was not an option, so Chung physically examined the video and monitored each bacterium and its offspring.

These tests demonstrated that the TB bacteria did not grow its cells according to typical patterns. Other bacterial species have exponential growth, meaning that smaller cells develop more slowly. Whether TB bacteria are small and newly formed or far along in their cell cycle and about to divide, their growth rates can be the same.

This is the first reported organism that can do this. TB’s behavior challenges fundamental bacterial biology as it is been thought that ribosomes which are sites of protein synthesis in the cell drive cell growth rates, but our work suggests that something else may be happening in TB bacteria that raises new questions about its growth control.” 

Eun Seon Chung, Postdoctoral Fellow, School of Medicine, Tufts University

The scientists found another unique growth behavior of TB bacteria: they can start growing from either end after birth, in addition to the wide variety in growth patterns among the individual bacterial cells. This was surprising because, during division, related bacteria only begin to grow from the end opposite the one where they pinched off their mother cell.

 Collectively, the findings challenge preconceived notions based on more homogeneous and faster-growing model organisms by showing that TB bacteria employ different tactics to enhance variety among their progeny.

According to Aldridge, the work will aid in the improved understanding and utilization of these pathways for therapeutic purposes by her lab and other research teams.

A lot of basic microbiology research is done in fast-growing model organisms, and while they are models for a reason, that does not make them representatives of other types of bacteria. There is an enormous diversity of life that we are not studying at the fundamental level and this work demonstrates why we need to study the pathogens themselves.”

Bree Aldridge, Professor and Study Co-Senior Author, School of Medicine, Tufts University