Small Noncoding RNAs MTS0997 and MTS1338 Affect the Adaptation and Virulence of Mycobacterium tuberculosis

Galina Shepelkova,Mikhail Averbakch Jr,Atadzhan Ergeshov,Vladimir Evstifeev,Ilya Sivokozov,Tatyana Azhikina,Vladimir Yeremeev

doi:10.3390/microbiolres12010014

Abstract

Tuberculosis (TB) is currently the leading cause of death among bacterial infectious diseases. The spectrum of disease manifestations depends on both host immune responses and the ability of Mycobacterium tuberculosis to resist it. Small non-coding RNAs are known to regulate gene expression; however, their functional role in the relationship of M. tuberculosis with the host is poorly understood. Here, we investigated the effect of small non-coding sRNAs MTS1338 and MTS0997 on M. tuberculosis properties by creating knockout strains. We also assessed the effect of small non-coding RNAs on the survival of wild type and mutant mycobacteria in primary cultures of human alveolar macrophages and the virulence of these strains in a mouse infection model. Wild-type and mutants survived differentially in human alveolar macrophages. Infection of I/St mice with KO M. tuberculosis H37RV strains provided beneficial effects onto major TB phenotypes. We observed attenuated tuberculosis-specific inflammatory responses, including reduced cellular infiltration and decreased granuloma formation in the lungs. Infections caused by KO strains were characterized by significantly lower inflammation of mouse lung tissue and increased survival time of infected animals. Thus, the deletion of MTS0997 and MTS1338 lead to a significant decrease in the virulence of M. tuberculosis.

Highlights

Mycobacterium tuberculosis is one of the most successful human pathogens, which causes more deaths than any other single infectious agent
Protection against M. tuberculosis infection is largely ensured by the components of the innate immune system, resident alveolar, recruited macrophages, neutrophils, and dendritic cells [19]
When mycobacteria enter the alveolar space, alveolar macrophages (AM) trigger primary defense mechanisms aimed at fighting bacteria

Summary

Introduction

Mycobacterium tuberculosis is one of the most successful human pathogens, which causes more deaths than any other single infectious agent. The range of manifestations of TB infection depends both on the characteristics of the host’s immune response to the pathogen, and on the ability of mycobacteria to resist this response. After mycobacteria enter the host through the respiratory tract, both the development of active TB infection with the manifestation of clinical signs of tuberculosis, and asymptomatic “latent” TB infection with the presence of dormant M. tuberculosis is possible [2,3,4]. Inability of the immune system to protect the host from the pathogenic effects of mycobacteria depends on many factors; two main ones can be highlighted: immune system defects at various levels [5,6] and modulation of M. tuberculosis immune response that allows mycobacteria to survive, multiply, and cause a disease [7]

Methods

Results

Conclusion