Frequently arising ESX-1-associated phase variants influence Mycobacterium tuberculosis fitness in the presence of host and antibiotic pressures

• Published in: mBio Vol. 16; no. 3; p. e0376224
• Main Authors: Luna, Michael J., Oluoch, Peter O., Miao, Jiazheng, Culviner, Peter, Papavinasasundaram, Kadamba, Jaecklein, Eleni, Shell, Scarlet S., Ioerger, Thomas R., Fortune, Sarah M., Farhat, Maha R., Sassetti, Christopher M.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 12.03.2025
• Subjects: Animals; Antitubercular Agents - pharmacology; bacterial genetics; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Genetic Fitness; INDEL Mutation; Mice; Mycobacteriology; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - physiology; phase variation; Research Article; tuberculosis; Tuberculosis - microbiology; Type VII Secretion Systems - genetics; Type VII Secretion Systems - metabolism; bacterial genetics; tuberculosis; phase variation
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.03762-24

Mycobacterium tuberculosis (Mtb) is responsible for more deaths worldwide than any other single infectious agent. Understanding how this pathogen adapts to the varied environmental pressures imposed by host immunity and antibiotics has important implications for the design of more effective therapies. In this work, we show that the genome of Mtb contains multiple contingency loci that control the activity of the ESX-1 secretion system, which is critical for interactions with the host. These loci consist of homopolymeric DNA tracts in gene regulatory regions that are subject to high-frequency reversible variation and act to tune the activity of ESX-1. We find that variation at these sites increases the fitness of Mtb in the presence of antibiotic and/or during infection. These findings indicate that Mtb has the ability to diversify its genome in specific sites to create subpopulations of cells that are preadapted to new conditions.