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bioRxiv · 10.1101/2025.01.30.635747

Candidate transmission survival genome of Mycobacterium tuberculosis

Mishra, S.·Singh, P. R.·Hu, X.·Lopez-Quezada, L.·Jinich, A.·Jahn, R.·Geurts, L.·Shen, N.·DeJesus, M.·Hartman, T.·Rhee, K. Y.·Zimmerman, M.·Dartois, V. A.·Jones, R. M.·Jiang, X.·Almada-Monter, R.·Bourouiba, L.·Nathan, C. F.
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Abstract

Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through the air. To begin to understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water-soluble, lipidic and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome and protected Mtb from dying in microdroplets desiccating in air. Yet survival was not passive: Mtb appeared to rely on hundreds of genes to survive conditions associated with transmission. Essential genes subserving proteostasis offered most protection. A large number of conventionally nonessential genes appeared to contribute as well, including genes encoding proteins that resemble anti-desiccants. The candidate transmission survival genome of Mtb may offer opportunities to reduce transmission of tuberculosis. Significance StatementMycobacterium tuberculosis (Mtb) travels from the lungs of one person through the air to the lungs of another and survives multiple stresses en route, including changes in temperature and in concentrations of oxygen, carbon dioxide, hydrogen ions, salts and organic solutes. Here we present a genetically tractable model of transmission to begin the identification of the transmission survival genome of Mtb. We devised a fluid that mimics TB lesions, found that it protects Mtb from transmission-related stresses, associated this with the structure of the droplets as they dry and their ability to retain water, and used it to query the potential contribution of each of Mtbs genes to Mtbs survival in models of three sequential stages of transmission.

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Mishra, S., Singh, P. R., Hu, X., Lopez-Quezada, L., Jinich, A., Jahn, R., Geurts, L., Shen, N., DeJesus, M., Hartman, T., Rhee, K. Y., Zimmerman, M., Dartois, V. A., Jones, R. M., Jiang, X., Almada-Monter, R., Bourouiba, L., Nathan, C. F.. 2025-01-30. Candidate transmission survival genome of Mycobacterium tuberculosis. https://doi.org/10.1101/2025.01.30.635747

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