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Abstract
Small non-coding RNAs play a key role in bacterial adaptation to various stresses. Mycobacterium tuberculosis small RNA MTS1338 is upregulated during mycobacteria infection of macrophages, suggesting its involvement in the interaction of the pathogen with the host. In this study, we explored the functional effects of MTS1338 by expressing it in non-pathogenic Mycobacterium smegmatis that lacks the MTS1338 gene. The results indicated that MTS1338 slowed the growth of the recombinant mycobacteria in culture and increased their survival in RAW 264.7 macrophages, where the MTS1338-expressing strain significantly (p < 0.05) reduced the number of mature phagolysosomes and changed the production of cytokines IL-1β, IL-6, IL-10, IL-12, TGF-β, and TNF-α compared to those of the control strain. Proteomic and secretomic profiling of recombinant and control strains revealed differential expression of proteins involved in the synthesis of main cell wall components and in the regulation of iron metabolism (ESX-3 secretion system) and response to hypoxia (furA, whiB4, phoP). These effects of MTS1338 expression are characteristic for M. tuberculosis during infection, suggesting that in pathogenic mycobacteria MTS1338 plays the role of a virulence factor supporting the residence of M. tuberculosis in the host.
Highlights
Tuberculosis (TB) remains a major threat to global public health, with at least 10 million new cases and 1.2 million deaths in 2019 (World Health Organization’s Global TBReport, 2019, https://www.who.int/tb/publications/global_report/en/)
Accumulating evidence indicates that mycobacteria can control host defense mechanisms by expressing small regulatory RNAs, which interfere with mRNA translation and stability
The results indicated that MTS1338 expression in MSmeg slightly slowed down bacterial proliferation in liquid medium (Figure 1A) and at the same time promoted survival of mycobacteria within RAW264.7 macrophages, as indicated by the growth of the recombinant MTS1338-expressing and control strains isolated from macrophages and plated on solid medium (Figure 1B)
Summary
Tuberculosis (TB) remains a major threat to global public health, with at least 10 million new cases and 1.2 million deaths in 2019 MTS1338 overexpression in MTb increased bacterial resistance to the stressful effects of hydrogen peroxide, nitric oxide, acidic environment, and long-term starvation [12,13] These findings suggest that MTS1338 may promote the survival of mycobacteria in infected macrophages by triggering the transcriptional changes necessary for MTb adaptation to the hostile intracellular environment. Our results indicate that MTS1338 upregulates the enzymes responsible for the synthesis of the mycobacterial cell envelope and promotes the survival of MSmeg in macrophages, in which the MTS1338-expressing MSmeg induces phagosome maturation arrest and modulates the expression of pro-inflammatory cytokines These changes are characteristic for pathogenic MTb upon infection, suggesting a role of MTS1338 in MTb virulence
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