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Small RNAs of Mycobacterium tuberculosis Regulate Pathogen Virulence and Host Immune Responses
Mycobacterium tuberculosis, the causative agent of tuberculosis, determines the severity of infection not only through virulent proteins but also through small regulatory RNAs. Researchers from the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, together with colleagues from the Bach Institute of Biochemistry of the Research Center of Biotechnology of the Russian Academy of Sciences and the Central Tuberculosis Research Institute, studied two such molecules, MTS0997 and MTS1338, and showed that they simultaneously affect pathogen properties and shape the host immune response.
The scientists generated mutant mycobacterial strains with deletions of one or both of these RNAs and then studied them in macrophages and in mice. The results were unexpected: deletion of the regulatory RNAs did not attenuate the infection but, on the contrary, enhanced it. Mice infected with the mutant strains died faster, although the number of bacteria in the lungs remained comparable to that in the control group.
Deletion of MTS0997 had a more pronounced effect on the mycobacteria than deletion of MTS1338. In the mutant strain, the expression of genes involved in energy metabolism and respiration was altered, potentially helping the bacteria survive under oxygen-limited conditions, such as those inside macrophages or tuberculous granulomas. In addition, the activity of the ESX-1 secretion system, which contributes to host-cell damage and increased bacterial virulence, was enhanced. The mutant bacteria also altered the activity of macrophages and immune cells in the lungs. The expression of several pro-inflammatory mediators, including IL-6, IL-12, and IFN-γ, was reduced, while the double deletion led to a decrease in the number of CD4⁺ T cells.
This study demonstrates that small non-coding bacterial RNAs can act as important regulators of infection. They help M. tuberculosis reprogram its metabolism, regulate the expression of virulence factors, and modulate the host immune response.
This work was supported by Russian Science Foundation Grant No. 22-14-00235 and published in Frontiers in Cellular and Infection Microbiology.
october 27