M. tuberculosis Chooses Growth Over Dormancy in the Infected Lung

Review written by: Megan Mauriello

Tuberculosis is still a major infectious disease on a global scale, killing the most people of any infectious disease annually. Despite how long it has been known as the causative agent, Mycobacterium tuberculosis physiology and adaptation in the context of the disease is still poorly understood, largely because axenic culture systems fail to replicate the complexities of the disease. M. tuberculosis primarily infects the lungs, and when macrophages phagocytose the cells, they facilitate the formation of lesions called granulomas, rather than clearing the infection. Granulomas are heterogeneous, with microenvironments of different oxygen levels, reactive oxygen and nitrogen species, pH, and nutrient levels.

The authors postulate that, during acute infection, M. tuberculosis cells are transcriptionally optimized for survival and growth rather than dormancy. Indeed, their data demonstrates that bacteria continued active transcription and translation, employed stress responses, and metabolism geared towards energy conservation. Downregulation of DosR-regulated genes reflects a transcriptomic focus on active growth rather than dormancy and persistence.

Figure. Key biological processes of Mtb were altered in rabbit lungs. (A) Bar graph showing significantly affected biological processes of Mtb in the lungs, compared to the broth cultures. The x-axis denotes the adjusted p-value of significance, and the y-axis shows enriched biological processes. The number of Mtb genes involved in each of the biological processes is indicated next to the corresponding bars. (B) Interaction map showing the link between different biological functions as mentioned in (A). The size of the circle is proportionate to the number of genes, and the color code is based on the p-value of significance.BFP- negative and mCherry-positive cell population was sorted via fluorescence-activated cell sorting (FACS). EGFP knockdown was confirmed in this sorted subpopulation. Source data are provided as a Source Data file.

Enrichment of transcriptional regulators and RNA-associated processes, RNA-processing, ncRNA-related factors, and methylation-related pathways suggests that the host environment prompts heavy regulatory rewiring in the bacterium. Other transcriptional responses suggest that M. tuberculosis requires extensive genome protection in the lungs. Enrichment of transposases and recombination-associated genes reflects the importance of genome plasticity for adaptation to such an inhospitable environment. Interestingly, many canonical stress-response genes were actually downregulated, possibly because the lung environment is heterogeneous and therefore promotes physiological heterogeneity in the M. tuberculosis population.

Metabolic reprogramming suggested a strategy of energy conservation via increased nitrogen and carbon metabolism and cyclic nucleotide sequencing. Upregulation of redox-related pathways likely reflect the fluctuating oxygen concentration in the lungs. Lipid metabolism, secondary metabolite biosynthesis, antigenic variation and modulation, and virulence factors were upregulated, all of which play roles in protection from and evasion of the immune system. Fatty acid elongation pathways were downregulated, suggesting an emphasis on cell envelope remodeling over biomass production.

This study is the first microarray-based genome-wide transcriptomic profiling of M. tuberculosis during progressive pulmonary tuberculosis in rabbit lungs. This system is much more reflective of a human clinical infection than standard laboratory M. tuberculosis models. The results hint at new potential therapeutic targets for anti-tuberculosis drugs, especially ones which target active growth processes rather than maintenance of dormancy.

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READ MORE: Bhargavi G, Ghanny S, Soteropoulous P, Vetrivel U, Jayaraman R and Subbian S (2026) Genome-wide transcriptional landscape of Mycobacterium tuberculosis during acute lung infection. Front. Immunol. 17:1875227. doi: 10.3389/fimmu.2026.1875227