Genes required for Mycobacterium tuberculosis to survive the transition from aerosol to pulmonary alveolar lining fluid and early infection in a model of transmission

Prabhat Ranjan Singh, Martin Gengenbacher, Saurabh Mishra, Adrian Jinich, Xiuju Jiang, Felipe Tsang, Melissa Cristaldo, Michael DeJesus, Kyu Y. Rhee, Robert J. Kaner, Philip L. Leopold, Ronald G. Crystal, Dipak Kathayat, Brian C. VanderVen, Carl Nathan
2025 · doi:10.1101/2025.09.15.676370
preprint OA: closed CC-BY-NC-4.0
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This study identified genes essential for *Mycobacterium tuberculosis* to survive the transition from aerosol to pulmonary alveolar lining fluid and establish early infection in a mouse model.

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The paper investigates which Mtb genes enable survival during the transition from aerosol desiccation to rehydration in pulmonary alveolar lining fluid (ALF) and early infection. Using an in vitro model of ALF composition derived from human bronchoalveolar lavage fluid (BALF), the authors compared MALF with reconstituted BALF (rcBALF) and found that log-phase Mtb survived in both for at least 24 hours, whereas transmission-stage Mtb lost viability after 3 hours in MALF. Genome-wide CRISPRi screening identified 35 genes uniquely required for survival during the desiccated microdroplet-to-rehydration transition in MALF, with many non-essential in standard lab conditions and some of unknown function, and 13 of these genes were also required for survival in macrophage-like cells at an air-liquid interface with pulmonary epithelial cells. The study relies on model alveolar lining fluid and reconstituted lavage conditions rather than direct in vivo measurement. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Mycobacterium tuberculosis (Mtb) must survive multiple changes in environment for aerosol transmission. Our genome-wide screen for rehydration of modeled aerosols in surrogate pulmonary alveolar lining fluid identified a survival-sustaining role for 22 genes not required for survival during earlier stages of transmission, 20 of which are non-essential in routine culture. Thirteen genes were also needed for Mtb to survive in alveolar macrophages after passing through the earlier stages of transmission. Nine 9 of the 13 were needed for full infectivity of aerosols in mice. Seven of the genes sustaining the intra-alveolar survival of aerosolized Mtb are likely to regulate Mtb’s uptake, catabolism or synthesis of lipids as regulated by cAMP. Our results reveal a dynamic form of conditional essentiality that only emerges after bacteria experience a sequence of other pathophysiologically relevant conditions. These findings enlarge Mtb’s candidate transmission survival genome with stage-specific genes encoding potential targets for blocking tuberculosis transmission.
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Abstract Mycobacterium tuberculosis (Mtb) must withstand physical and chemical stresses during airborne transmission, including during the desiccation of aerosols small enough to reach pulmonary alveoli in a new host. There, Mtb encounters an antimicrobial pulmonary alveolar lining fluid (ALF) before it is engulfed by macrophages. To study the genes involved in Mtb’s ability to survive the transition from desiccated droplet to pulmonary alveolus in an in vitro model, we formulated a model alveolar lining fluid (MALF) that mimics the composition of ALF as inferred from human bronchoalveolar lavage fluid (BALF). We compared the transcriptome of log-phase Mtb in MALF to the transcriptome of Mtb in BALF as BALF from the lungs of healthy adults was reconstituted to compensate for the dilution of ALF by lavage (rcBALF). Mtb from log-phase culture in a standard laboratory medium survived quantitatively in MALF and rcBALF for at least 24 hours. In contrast, Mtb that had passed through earlier stages of transmission began to succumb after 3 hours in MALF, past the time when particles have been observed to be phagocytized by alveolar macrophages. Screening of a genome-wide CRISPRi library of Mtb identified 35 genes as uniquely required by Mtb to survive the transition from desiccated microdroplet into rehydration in MALF. Thirty-one of these genes are non-essential under conventional laboratory conditions and seven have unknown functions. Thirteen of the 35 genes were additionally required for Mtb to survive in macrophage-like cells cultured at the air-liquid interface with pulmonary epithelial cells. This study nominates additional members of the transmission survival genome of Mtb, illustrates that different genes may contribute to the survival of Mtb at different stages of transmission, and suggests that modeled transmission can shed light on the functions of Mtb genes whose contributions have been unknown. Competing Interest Statement The authors have declared no competing interest.

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[{'doi': None, 'name': None, 'awards': ['P01AI159402']}, {'doi': None, 'name': None, 'awards': ['P30 AI168433']}, {'doi': '10.13039/100017922', 'name': 'Potts Memorial Foundation', 'awards': ['n/a']}, {'doi': None, 'name': 'Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine', 'awards': ['n/a']}, {'doi': None, 'name': None, 'awards': ['INV-070075']}, {'doi': '10.13039/100000060', 'name': 'National Institute of Allergy and Infectious Diseases', 'awards': []}]

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License: CC-BY-NC-4.0