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MTS1338, A Small Mycobacterium tuberculosis RNA, Regulates Transcriptional Shifts Consistent With Bacterial Adaptation for Entering Into Dormancy and Survival Within Host Macrophages.

ABSTRACT: Small non-coding RNAs play a significant role in bacterial adaptation to changing environmental conditions. We investigated the dynamics of expression of MTS1338, a small non-coding RNA of Mycobacterium tuberculosis, in the mouse model in vivo, regulation of its expression in the infected macrophages, and the consequences of its overexpression in bacterial cultures. Here we demonstrate that MTS1338 significantly contributes to host-pathogen interactions. Activation of the host immune system triggered NO-inducible up-regulation of MTS1338 in macrophage-engulfed mycobacteria. Constitutive overexpression of MTS1338 in cultured mycobacteria improved their survival in vitro under low pH conditions. MTS1338 up-regulation launched a spectrum of shifts in the transcriptome profile similar to those reported for M. tuberculosis adaptation to hostile intra-macrophage environment. Using the RNA-seq approach, we demonstrate that gene expression changes accompanying MTS1338 overexpression indicate reduction in translational activity and bacterial growth. These changes indicate mycobacteria entering the dormant state. Taken together, our results suggest a direct involvement of this sRNA in the interplay between mycobacteria and the host immune system during infectious process.

SUBMITTER: Salina EG

PROVIDER: S-EPMC6901956 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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MTS1338, A Small Mycobacterium tuberculosis RNA, Regulates Transcriptional Shifts Consistent With Bacterial Adaptation for Entering Into Dormancy and Survival Within Host Macrophages.

Salina Elena G EG Grigorov Artem A Skvortsova Yulia Y Majorov Konstantin K Bychenko Oksana O Ostrik Albina A Logunova Nadezhda N Ignatov Dmitriy D Kaprelyants Arseny A Apt Alexander A Azhikina Tatyana T

Frontiers in cellular and infection microbiology 20191126

Small non-coding RNAs play a significant role in bacterial adaptation to changing environmental conditions. We investigated the dynamics of expression of MTS1338, a small non-coding RNA of Mycobacterium tuberculosis, in the mouse model in vivo, regulation of its expression in the infected macrophages, and the consequences of its overexpression in bacterial cultures. Here we demonstrate that MTS1338 significantly contributes to host-pathogen interactions. Activation of the host immu ...[more]

PMID: 31850238

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Project description:BackgroundTuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb) remains a significant health problem worldwide with a third of the world population infected and nearly nine million new cases claiming 1.1 million deaths every year. The outcome following infection by Mtb is determined by a complex and dynamic host-pathogen interaction in which the phenotype of the pathogen and the immune status of the host play a role. However, the molecular mechanism by which Mtb strains induce different responses during intracellular infection of the host macrophage is not fully understood. To explore the early molecular events triggered upon Mtb infection of macrophages, we studied the transcriptional responses of murine bone marrow-derived macrophages (BMM) to infection with two clinical Mtb strains, CDC1551 and HN878. These strains have previously been shown to differ in their virulence/immunogenicity in the mouse and rabbit models of pulmonary TB.ResultsIn spite of similar intracellular growth rates, we observed that compared to HN878, infection by CDC1551 of BMM was associated with an increased global transcriptome, up-regulation of a specific early (6 hours) immune response network and significantly elevated nitric oxide production. In contrast, at 24 hours post-infection of BMM by HN878, more host genes involved in lipid metabolism, including cholesterol metabolism and prostaglandin synthesis were up-regulated, compared to infection with CDC1551.In association with the differences in the macrophage responses to infection with the 2 Mtb strains, intracellular CDC1551 expressed higher levels of stress response genes than did HN878.ConclusionsIn association with the early and more robust macrophage activation, intracellular CDC1551 cells were exposed to a higher level of stress leading to increased up-regulation of the bacterial stress response genes. In contrast, sub-optimal activation of macrophages and induction of a dysregulated host cell lipid metabolism favored a less stressful intracellular environment for HN878. Our findings suggest that the ability of CDC1551 and HN878 to differentially activate macrophages during infection probably determines their ability to either resist host cell immunity and progress to active disease or to succumb to the host protective responses and be driven into a non-replicating latent state in rabbit lungs.

Project description:UnlabelledStrong evidence supports the idea that fatty acids rather than carbohydrates are the main energy source of Mycobacterium tuberculosis during infection and latency. Despite that important role, a complete scenario of the bacterium's metabolism when lipids are the main energy source is still lacking. Here we report the development of an in vitro model to analyze adaptation of M. tuberculosis during assimilation of long-chain fatty acids as sole carbon sources. The global lipid transcriptome revealed a shift toward the glyoxylate cycle, the overexpression of main regulators whiB3, dosR, and Rv0081, and the increased expression of several genes related to reductive stress. Our evidence showed that lipid storage seems to be the selected mechanism used by M. tuberculosis to ameliorate the assumed damage of reductive stress and that concomitantly the bacilli acquired a slowed-growth and drug-tolerant phenotype, all characteristics previously associated with the dormant stage. Additionally, intergenic regions were also detected, including the unexpected upregulation of tRNAs that suggest a new role for these molecules in the acquisition of a drug-tolerant phenotype by dormant bacilli. Finally, a set of lipid signature genes for the adaptation process was also identified. This in vitro model represents a suitable condition to illustrate the participation of reductive stress in drugs' activity against dormant bacilli, an aspect scarcely investigated to date. This approach provides a new perspective to the understanding of latent infection and suggests the participation of previously undetected molecules.ImportanceMycobacterium tuberculosis establishes long-lasting highly prevalent infection inside the human body, called latent tuberculosis. The known involvement of fatty acids is changing our understanding of that silent infection; however, question of how tubercle bacilli globally adapt to a lipid-enriched environment is still an unanswered. With the single change of providing fatty acids as carbon sources, the bacilli switch on their program related to dormant stage: slowed growth, accumulation of lipid bodies, and development of drug tolerance. In this stage, unexpected and previously unknown participants were found to play putatively important roles during the process. For the first time, this work compares the global transcriptomics of bacteria by using strand-specific RNA sequencing under two different growth conditions. This study suggests novel targets for the control of tuberculosis and provides a new straightforward in vitro model that could help to test the activity of drugs against dormant bacilli from a novel perspective.

Dataset Information

MTS1338, A Small Mycobacterium tuberculosis RNA, Regulates Transcriptional Shifts Consistent With Bacterial Adaptation for Entering Into Dormancy and Survival Within Host Macrophages.

Publications

MTS1338, A Small <i>Mycobacterium tuberculosis</i> RNA, Regulates Transcriptional Shifts Consistent With Bacterial Adaptation for Entering Into Dormancy and Survival Within Host Macrophages.

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