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11 pages, 1859 KiB

Open AccessArticle

MicroRNAs as Biomarkers of Active Pulmonary TB Course

by Galina S. Shepelkova, Vladimir V. Evstifeev, Ruslan V. Tarasov, Anush E. Ergeshova, Mamed A. Bagirov and Vladimir V. Yeremeev

Microorganisms 2023, 11(3), 626; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms11030626 - 28 Feb 2023

Cited by 5 | Viewed by 1381

Abstract

The spread of drug-resistant forms of TB dictates the need for surgical treatment in the complex of anti-tuberculosis measures in Russia. Most often, surgical intervention is performed in the case of pulmonary tuberculoma or fibrotic cavitary tuberculosis (FCT). This study is devoted to [...] Read more.

The spread of drug-resistant forms of TB dictates the need for surgical treatment in the complex of anti-tuberculosis measures in Russia. Most often, surgical intervention is performed in the case of pulmonary tuberculoma or fibrotic cavitary tuberculosis (FCT). This study is devoted to the search for biomarkers that characterize the course of disease in surgical TB patients. It is assumed that such biomarkers will help the surgeon decide on the timing of the planned operation. A number of serum microRNAs, potential regulators of inflammation and fibrosis in TB, selected on the basis of PCR-Array analysis, were considered as biomarkers. Quantitative real time polymerase chain reaction and receiver operating curves (ROC) were used to verify Array data and to estimate the ability of microRNAs (miRNAs) to discriminate between healthy controls, tuberculoma patients, and FCT patients. The study showed that miR-155, miR-191 and miR-223 were differentially expressed in serum of tuberculoma with “decay” and tuberculoma without “decay” patients. Another combination (miR-26a, miR-191, miR-222 and miR-320) forms a set to differentiate between tuberculoma with “decay” and FCT. Patients with tuberculoma without “decay” diagnosis differ from those with FCT in serum expression of miR-26a, miR-155, miR-191, miR-222 and miR-223. Further investigations are required to evaluate these sets on a larger population so as to set cut-off values that could be applied in laboratory diagnosis. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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15 pages, 2313 KiB

Open AccessArticle

Epidemiology and Drug Resistance Patterns of Mycobacterium tuberculosis in High-Burden Area in Western Siberia, Russia

by Irina Kostyukova, Oksana Pasechnik and Igor Mokrousov

Microorganisms 2023, 11(2), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms11020425 - 08 Feb 2023

Cited by 5 | Viewed by 2022

Abstract

Russia is a high-burden area for multidrug-resistant tuberculosis (MDR-TB). Here, we studied the epidemiological situation and drug resistance patterns of Mycobacterium tuberculosis in the Omsk region in Western Siberia. M. tuberculosis isolates (n = 851) were recovered from newly diagnosed TB patients [...] Read more.

Russia is a high-burden area for multidrug-resistant tuberculosis (MDR-TB). Here, we studied the epidemiological situation and drug resistance patterns of Mycobacterium tuberculosis in the Omsk region in Western Siberia. M. tuberculosis isolates (n = 851) were recovered from newly diagnosed TB patients in 2021. The isolates were tested by bacteriological and molecular methods, and long-term epidemiological data were analyzed. The TB incidence dec, this is not variablereased from 93.9 in 2012 to 48.1 in 2021, per 100,000 population, but the primary MDR-TB rate increased from 19.2% to 26.4%. The destructive forms of tuberculosis accounted for 37.8% of all cases, while 35.5% of patients were smear-positive. Of all isolates tested, 55.2% were culture-positive, of which 94.5% were further tested for phenotypic drug resistance and associated mutations. More than half (53.4%) of isolates were drug-resistant, 13.9% were monoresistant and 67.9% were MDR. Among MDR isolates, 40.4% were pre-XDR, and 19.2% were XDR. The spectrum of drug resistance included second-line drugs (new-generation fluoroquinolones, linezolid), which significantly increase the risk of an adverse outcome in patients. In conclusion, our results highlight the critical importance of monitoring drug resistance in circulating M. tuberculosis strains emerging due to ineffective treatment and active transmission. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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16 pages, 2522 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

by Denis Lagutkin, Anna Panova, Anatoly Vinokurov, Alexandra Gracheva, Anastasia Samoilova and Irina Vasilyeva

Microorganisms 2022, 10(7), 1440; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10071440 - 17 Jul 2022

Cited by 5 | Viewed by 2784

Abstract

The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug [...] Read more.

The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug resistance in MTB and to observe which polymorphisms emerge in MTB genomes after anti-tuberculosis treatment. We performed whole-genome sequencing of 152 MTB isolates including 70 isolates as 32 series of pre- and post-treatment MTB. Based on genotypes and phenotypic drug susceptibility, we conducted phylogenetic convergence-based genome-wide association study (GWAS) with streptomycin-, isoniazid-, rifampicin-, ethambutol-, fluoroquinolones-, and aminoglycosides-resistant MTB against susceptible ones. GWAS revealed statistically significant associations of SNPs within Rv2820c, cyp123 and indels in Rv1269c, Rv1907c, Rv1883c, Rv2407, Rv3785 genes with resistant MTB phenotypes. Comparisons of serial isolates showed that treatment induced different patterns of intra-host evolution. We found indels within Rv1435c and ppsA that were not lineage-specific. In addition, Beijing-specific polymorphisms within Rv0036c, Rv0678, Rv3433c, and dop genes were detected in post-treatment isolates. The appearance of Rv3785 frameshift insertion in 2 post-treatment strains compared to pre-treatment was also observed. We propose that the insertion within Rv3785, which was a GWAS hit, might affect cell wall biosynthesis and probably mediates a compensatory mechanism in response to treatment. These results may shed light on the mechanisms of MTB adaptation to chemotherapy and drug resistance formation. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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17 pages, 10589 KiB

Open AccessArticle

Biodiversity of Mycobacterium tuberculosis in Bulgaria Related to Human Migrations or Ecological Adaptation

by Stefan Panaiotov, Dzheni Madzharov and Yordan Hodzhev

Microorganisms 2022, 10(1), 146; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10010146 - 11 Jan 2022

Cited by 4 | Viewed by 2463

Abstract

Bulgaria is among the 18 high-priority countries of the WHO European Region with high rates of tuberculosis. The causative agent of tuberculosis is thought to have emerged in Africa 70,000 years ago, or during the Neolithic age, and colonized the world through human [...] Read more.

Bulgaria is among the 18 high-priority countries of the WHO European Region with high rates of tuberculosis. The causative agent of tuberculosis is thought to have emerged in Africa 70,000 years ago, or during the Neolithic age, and colonized the world through human migrations. The established main lineages of tuberculosis correlate highly with geography. The goal of our study was to investigate the biodiversity of Mycobacteriumtuberculosis in Bulgaria in association with human migration history during the last 10 centuries. We analyzed spoligotypes and MIRU-VNTR genotyping data of 655 drug-sensitive and 385 multidrug-resistant M. tuberculosis strains collected in Bulgaria from 2008 to 2018. We assigned the genotype of all isolates using SITVITWEB and MIRU-VNTRplus databases and software. We investigated the major well-documented historical events of immigration to Bulgaria that occurred during the last millennium. Genetic profiles demonstrated that, with the exceptions of 3 strains of Mycobacterium bovis and 18 strains of Lineage 2 (W/Beijing spoligotype), only Lineage 4 (Euro-American) was widely diffused in Bulgaria. Analysis of well-documented immigrations of Roma from the Indian subcontinent during the 10th to the 12th centuries, Turkic peoples from Central Asia in the medieval centuries, and more recently Armenians, Russians, and Africans in the 20th century influenced the biodiversity of M. tuberculosis in Bulgaria but only with genotypes of sublineages within the L4. We hypothesize that these sublineages were more virulent, or that ecological adaptation of imported M. tuberculosis genotypes was the main driver contributing to the current genetic biodiversity of M. tuberculosis in Bulgaria. We also hypothesize that some yet unknown local environmental factors may have been decisive in the success of imported genotypes. The ecological factors leading to local genetic biodiversity in M. tuberculosis are multifactorial and have not yet been fully clarified. The coevolution of long-lasting pathogen hosts should be studied, taking into account environmental and ecological changes. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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17 pages, 2152 KiB

Open AccessArticle

Mycobacterium tuberculosis Small RNA MTS1338 Confers Pathogenic Properties to Non-Pathogenic Mycobacterium smegmatis

by Oksana Bychenko, Yulia Skvortsova, Rustam Ziganshin, Artem Grigorov, Leonid Aseev, Albina Ostrik, Arseny Kaprelyants, Elena G. Salina and Tatyana Azhikina

Microorganisms 2021, 9(2), 414; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9020414 - 17 Feb 2021

Cited by 7 | Viewed by 2535

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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Review

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16 pages, 660 KiB

Open AccessReview

Fighting Tuberculosis: In Search of a BCG Replacement

by Nonna I. Nadolinskaia, Maria S. Kotliarova and Anna V. Goncharenko

Microorganisms 2023, 11(1), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms11010051 - 23 Dec 2022

Cited by 4 | Viewed by 1993

Abstract

Tuberculosis is one of the most threatening infectious diseases and represents an important and significant reason for mortality in high-burden regions. The only licensed vaccine, BCG, is hardly capable of establishing long-term tuberculosis protection and is highly variable in its effectiveness. Even after [...] Read more.

Tuberculosis is one of the most threatening infectious diseases and represents an important and significant reason for mortality in high-burden regions. The only licensed vaccine, BCG, is hardly capable of establishing long-term tuberculosis protection and is highly variable in its effectiveness. Even after 100 years of BCG use and research, we still cannot unequivocally answer the question of which immune correlates of protection are crucial to prevent Mycobacterium tuberculosis (Mtb) infection or the progression of the disease. The development of a new vaccine against tuberculosis arises a nontrivial scientific challenge caused by several specific features of the intracellular lifestyle of Mtb and the ability of the pathogen to manipulate host immunity. The purpose of this review is to discuss promising strategies and the possibilities of creating a new vaccine that could replace BCG and provide greater protection. The considered approaches include supplementing mycobacterial strains with immunodominant antigens and genetic engineering aimed at altering the interaction between the bacterium and the host cell, such as the exit from the phagosome. Improved new vaccine strains based on BCG and Mtb undergoing clinical evaluation are also overviewed. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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23 pages, 850 KiB

Open AccessReview

Mycobacterium tuberculosis Dormancy: How to Fight a Hidden Danger

by Elena G. Salina and Vadim Makarov

Microorganisms 2022, 10(12), 2334; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10122334 - 25 Nov 2022

Cited by 5 | Viewed by 2145

Abstract

Both latent and active TB infections are caused by a heterogeneous population of mycobacteria, which includes actively replicating and dormant bacilli in different proportions. Dormancy substantially affects M. tuberculosis drug tolerance and TB clinical management due to a significant decrease in the metabolic [...] Read more.

Both latent and active TB infections are caused by a heterogeneous population of mycobacteria, which includes actively replicating and dormant bacilli in different proportions. Dormancy substantially affects M. tuberculosis drug tolerance and TB clinical management due to a significant decrease in the metabolic activity of bacilli, which leads to the complexity of both the diagnosis and the eradication of bacilli. Most diagnostic approaches to latent infection deal with a subpopulation of active M. tuberculosis, underestimating the contribution of dormant bacilli and leading to limited success in the fight against latent TB. Moreover, active TB appears not only as a primary form of infection but can also develop from latent TB, when resuscitation from dormancy is followed by bacterial multiplication, leading to disease progression. To win against latent infection, the identification of the Achilles’ heel of dormant M. tuberculosis is urgently needed. Regulatory mechanisms and metabolic adaptation to growth arrest should be studied using in vitro and in vivo models that adequately imitate latent TB infection in macroorganisms. Understanding the mechanisms underlying M. tuberculosis dormancy and resuscitation may provide clues to help control latent infection, reduce disease severity in patients, and prevent pathogen transmission in the population. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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28 pages, 5504 KiB

Open AccessReview

Analogues of Pyrimidine Nucleosides as Mycobacteria Growth Inhibitors

by Liudmila A. Alexandrova, Anastasia L. Khandazhinskaya, Elena S. Matyugina, Dmitriy A. Makarov and Sergey N. Kochetkov

Microorganisms 2022, 10(7), 1299; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms10071299 - 27 Jun 2022

Cited by 9 | Viewed by 2152

Abstract

Tuberculosis (TB) is the oldest human infection disease. Mortality from TB significantly decreased in the 20th century, because of vaccination and the widespread use of antibiotics. However, about a third of the world’s population is currently infected with Mycobacterium tuberculosis (Mtb) [...] Read more.

Tuberculosis (TB) is the oldest human infection disease. Mortality from TB significantly decreased in the 20th century, because of vaccination and the widespread use of antibiotics. However, about a third of the world’s population is currently infected with Mycobacterium tuberculosis (Mtb) and the death rate from TB is about 1.4–2 million people per year. In the second half of the 20th century, new extensively multidrug-resistant strains of Mtb were identified, which are steadily increasing among TB patients. Therefore, there is an urgent need to develop new anti-TB drugs, which remains one of the priorities of pharmacology and medicinal chemistry. The antimycobacterial activity of nucleoside derivatives and analogues was revealed not so long ago, and a lot of studies on their antibacterial properties have been published. Despite the fact that there are no clinically used drugs based on nucleoside analogues, some progress has been made in this area. This review summarizes current research in the field of the design and study of inhibitors of mycobacteria, primarily Mtb. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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16 pages, 2549 KiB

Open AccessReview

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs

by José Manuel Ezquerra-Aznárez, Pedro E. Almeida da Silva and José A. Aínsa

Microorganisms 2021, 9(11), 2335; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9112335 - 11 Nov 2021

Cited by 3 | Viewed by 2336

Abstract

Antimicrobial resistance, the so-called silent pandemic, is pushing industry and academia to find novel antimicrobial agents with new mechanisms of action in order to be active against susceptible and drug-resistant microorganisms. In the case of tuberculosis, the need of novel anti-tuberculosis drugs [...] Read more.

Antimicrobial resistance, the so-called silent pandemic, is pushing industry and academia to find novel antimicrobial agents with new mechanisms of action in order to be active against susceptible and drug-resistant microorganisms. In the case of tuberculosis, the need of novel anti-tuberculosis drugs is specially challenging because of the intricate biology of its causative agent, Mycobacterium tuberculosis. The repurposing of medicines has arisen in recent years as a fast, low-cost, and efficient strategy to identify novel biomedical applications for already approved drugs. This review is focused on anti-parasitic drugs that have additionally demonstrated certain levels of anti-tuberculosis activity; along with this, natural products with a dual activity against parasites and against M. tuberculosis are discussed. A few clinical trials have tested antiparasitic drugs in tuberculosis patients, and have revealed effective dose and toxicity issues, which is consistent with the natural differences between tuberculosis and parasitic infections. However, through medicinal chemistry approaches, derivatives of drugs with anti-parasitic activity have become successful drugs for use in tuberculosis therapy. In summary, even when the repurposing of anti-parasitic drugs for tuberculosis treatment does not seem to be an easy job, it deserves attention as a potential contributor to fuel the anti-tuberculosis drug pipeline. Full article

(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Control & Treatment)

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