ISB Creates PerSort, a New Cell Sorting Technology Aimed at Studying Drug Tolerance and Shortening Tuberculosis Treatment

isbscience.org/news/2020/12/09/isb-creates-persort-a-new-cell-sorting-technology-aimed-at-studying-drug-tolerance-and-shortening-tuberculosis-treatment/

Tuberculosis is one of the deadliest infectious diseases on earth. Last year, 1.4 million people were killed by TB, and a quarter of the world’s population has a latent form of the disease – they have been infected with the pathogen that causes TB, but it remains dormant.

Now, imagine the challenge researchers and clinicians face as they try to single out and target that pathogen, but are thwarted because it keeps changing its disguise. The TB-causing bacteria Mycobacterium tuberculosis (MTB) is able to evade detection and eradication by presenting itself as different subpopulations, helping it survive and persist harsh conditions during infection.

“This cunning pathogen has the ability to enter ‘stealth mode,’ making it incredibly difficult to eradicate with treatment,” said Dr. Nitin Baliga, ISB senior vice president, director and professor, whose lab studies MTB. “Making matters worse, MTB is becoming deadlier as multidrug-resistant strains emerge.”

Because of MTB’s unique ability to escape detection and killing, researchers have been stymied. The pathogen has been able to sidestep the immune system’s response and antibacterial killing, and the persister cells are a major barrier to the timely and relapse-free treatment of TB.

ISB researchers have developed a new cell sorting technology, called PerSort, that isolates and characterizes dormant persisters that exist in MTB cultures. Characterizing this subpopulation has led to the understanding of the mechanisms by which MTB persisters emerge, and has unveiled the physiological basis for their dormant and multidrug-tolerant state.

“Phenotypic heterogeneity in bacteria is a Pandora’s Box within which lies solutions to relapse-free treatment for TB,” said Dr. Vivek Srinivas, a postdoctoral fellow in the Baliga Lab and first author of a paper describing PerSort published in the journal mSystems. “This paper and the technology PerSort contribute to the field by making it possible to isolate and study a heterogenous phenotype – the drug-tolerant cells from Mycobacterium cultures.”

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The research team further found that activating oxygen respiratory physiology eliminates pre-existing persister subpopulations, increasing the likelihood of rapid antibiotic killing of MTB under host-relevant stress.

“This is a major step forward for handling this deadly infectious disease,” said Dr. Eliza Peterson, a senior research scientist in the Baliga Lab. “PerSort serves as a new tool to study MTB peristers for enabling targeted strategies to improve and shorten the treatment of TB.”