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Microbiology Spectrum Feb 2014Rapid adaptation to changing environments is one of the keys to the success of microorganisms. Since infection is a dynamic process, it is possible to predict that... (Review)
Review
Rapid adaptation to changing environments is one of the keys to the success of microorganisms. Since infection is a dynamic process, it is possible to predict that Mycobacterium tuberculosis adaptation involves continuous modulation of its global transcriptional profile in response to the changing environment found in the human body. In the last 18 years several studies have stressed the role of sigma (σ) factors in this process. These are small interchangeable subunits of the RNA polymerase holoenzyme that are required for transcriptional initiation and that determine promoter specificity. The M. tuberculosis genome encodes 13 of these proteins, one of which--the principal σ factor σA--is essential. Of the other 12 σ factors, at least 6 are required for virulence. In this article we review our current knowledge of mycobacterial σ factors, their regulons, the complex mechanisms determining their regulation, and their roles in M. tuberculosis physiology and virulence.
Topics: Gene Expression Regulation, Bacterial; Humans; Mycobacterium tuberculosis; Sigma Factor; Virulence; Virulence Factors
PubMed: 26082107
DOI: 10.1128/microbiolspec.MGM2-0007-2013 -
Microbiology Spectrum Jun 2014Lipidomics is a distinct subspecialty of metabolomics concerned with hydrophobic molecules that organize into membranes. Most of the lipid classes present in... (Review)
Review
Lipidomics is a distinct subspecialty of metabolomics concerned with hydrophobic molecules that organize into membranes. Most of the lipid classes present in Mycobacterium tuberculosis are found only in Actinobacteria and show extreme structural diversity. This article highlights the conceptual basis and the practical challenges associated with the mass spectrometry-based lipidomic study of M. tuberculosis to solve basic questions about the virulence of this lipid-laden organism.
Topics: Lipid Metabolism; Lipids; Mass Spectrometry; Metabolomics; Mycobacterium tuberculosis
PubMed: 26103971
DOI: 10.1128/microbiolspec.MGM2-0033-2013 -
Microbiology Spectrum Nov 2016The interaction between the host and the pathogen is extremely complex and is affected by anatomical, physiological, and immunological diversity in the... (Review)
Review
The interaction between the host and the pathogen is extremely complex and is affected by anatomical, physiological, and immunological diversity in the microenvironments, leading to phenotypic diversity of the pathogen. Phenotypic heterogeneity, defined as nongenetic variation observed in individual members of a clonal population, can have beneficial consequences especially in fluctuating stressful environmental conditions. This is all the more relevant in infections caused by Mycobacterium tuberculosis wherein the pathogen is able to survive and often establish a lifelong persistent infection in the host. Recent studies in tuberculosis patients and in animal models have documented the heterogeneous and diverging trajectories of individual lesions within a single host. Since the fate of the individual lesions appears to be determined by the local tissue environment rather than systemic response of the host, studying this heterogeneity is very relevant to ensure better control and complete eradication of the pathogen from individual lesions. The heterogeneous microenvironments greatly enhance M. tuberculosis heterogeneity influencing the growth rates, metabolic potential, stress responses, drug susceptibility, and eventual lesion resolution. Single-cell approaches such as time-lapse microscopy using microfluidic devices allow us to address cell-to-cell variations that are often lost in population-average measurements. In this review, we focus on some of the factors that could be considered as drivers of phenotypic heterogeneity in M. tuberculosis as well as highlight some of the techniques that are useful in addressing this issue.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Genetic Heterogeneity; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Phenotype; Tuberculosis
PubMed: 27837741
DOI: 10.1128/microbiolspec.TBTB2-0021-2016 -
Genes Jan 2019There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With... (Review)
Review
There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With improvements in genome sequencing technology, it is now possible to study the genetic diversity of tuberculosis with much greater resolution. Although tuberculosis bacteria do not engage in horizontal gene transfer, the genome is far more variable than previously thought. The study of genome-wide variation in tuberculosis has improved our understanding of the evolutionary origins of tuberculosis, the arrival of tuberculosis in Latin America, the genetic determinants of drug resistance, and lineage-specific associations with important clinical phenotypes. This article reviews what is known about the arrival of tuberculosis in Latin America, the genetic diversity of tuberculosis in Latin America, and the genotypic determinants of clinical phenotypes.
Topics: Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; South America; Tuberculosis
PubMed: 30654542
DOI: 10.3390/genes10010053 -
Infection, Genetics and Evolution :... Jun 2012Tuberculosis (TB) has been affecting humans for millennia. There is increasing indication that human-adapted Mycobacterium tuberculosis complex (MTBC) has been... (Review)
Review
Tuberculosis (TB) has been affecting humans for millennia. There is increasing indication that human-adapted Mycobacterium tuberculosis complex (MTBC) has been co-evolving with different human populations. Some of the most important drivers of MTBC evolution have been the host immune response and human demography. These old selective forces have shaped many of the features of human TB we see today. Two new selective pressures have emerged only a few decades ago, namely HIV co-infection and the use of anti-TB drugs. Here we discuss how the emergence of HIV/TB and drug resistance could impact the long-term balance between MTBC and its human host, and how these changes might influence the future evolutionary trajectory of MTBC.
Topics: Antitubercular Agents; Coinfection; Drug Resistance, Bacterial; Evolution, Molecular; Genetic Variation; HIV Infections; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Selection, Genetic; Tuberculosis
PubMed: 21867778
DOI: 10.1016/j.meegid.2011.08.010 -
The Indian Journal of Medical Research Dec 2017Tuberculosis (TB) remains an escalating problem worldwide. The current diagnostic methods do not always guarantee reliable diagnosis. TB treatment is a time-consuming... (Review)
Review
Tuberculosis (TB) remains an escalating problem worldwide. The current diagnostic methods do not always guarantee reliable diagnosis. TB treatment is a time-consuming process that requires the use of several chemotherapeutics, to which mycobacteria are becoming increasingly resistant. This article focuses on the potential utility of biomarkers of mycobacterial origin with potential implications for TB diagnosis. Properly standardized indicators could become new diagnostic tools, improving and streamlining the identification of Mycobacterium tuberculosis infection and the implementation of appropriate therapy. These markers can also potentially provide a quick confirmation of effectiveness of new anti-mycobacterial drugs and TB vaccines, leading to a possible application in practice.
Topics: Antitubercular Agents; Biomarkers; Humans; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines
PubMed: 29664027
DOI: 10.4103/ijmr.IJMR_1441_16 -
Disease Models & Mechanisms Mar 2020Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells....
Lactate dehydrogenase A (LDHA) mediates interconversion of pyruvate and lactate, and increased lactate turnover is exhibited by malignant and infected immune cells. Hypoxic lung granuloma in -infected animals present elevated levels of and lactate. Such alterations in the metabolic milieu could influence the outcome of host- interactions. Given the central role of LDHA for tumorigenicity, targeting lactate metabolism is a promising approach for cancer therapy. Here, we sought to determine the importance of LDHA for tuberculosis (TB) disease progression and its potential as a target for host-directed therapy. To this end, we orally administered FX11, a known small-molecule NADH-competitive LDHA inhibitor, to -infected C57BL/6J mice and mice with hypoxic necrotizing lung TB lesions. FX11 did not inhibit growth in aerobic/hypoxic liquid culture, but modestly reduced the pulmonary bacterial burden in C57BL/6J mice. Intriguingly, FX11 administration limited replication and onset of necrotic lung lesions in mice. In this model, isoniazid (INH) monotherapy has been known to exhibit biphasic killing kinetics owing to the probable selection of an INH-tolerant bacterial subpopulation. However, adjunct FX11 treatment corrected this adverse effect and resulted in sustained bactericidal activity of INH against As a limitation, LDHA inhibition as an underlying cause of FX11-mediated effect could not be established as the on-target effect of FX11 was unconfirmed. Nevertheless, this proof-of-concept study encourages further investigation on the underlying mechanisms of LDHA inhibition and its significance in TB pathogenesis.
Topics: Animals; Disease Models, Animal; Female; Host-Pathogen Interactions; Isoniazid; Mice, Inbred C57BL; Mycobacterium tuberculosis; Naphthalenes
PubMed: 32034005
DOI: 10.1242/dmm.041954 -
ACS Infectious Diseases Aug 2019MTBVAC is a live attenuated vaccine constructed by genetic deletions in the and virulence genes. The MTBVAC vaccine is currently in phase 2 clinical trials with... (Comparative Study)
Comparative Study
MTBVAC is a live attenuated vaccine constructed by genetic deletions in the and virulence genes. The MTBVAC vaccine is currently in phase 2 clinical trials with newborns and adults in South Africa, one of the countries with the highest incidence. Although MTBVAC has been extensively characterized by genomics, transcriptomics, lipidomics, and proteomics, its metabolomic profile is yet unknown. Accordingly, in this study we aim to identify differential metabolites between and MTBVAC. To this end, an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry was implemented in order to explore the main metabolic differences between and MTBVAC. As an outcome, we identified a set of 34 metabolites involved in diverse bacterial biosynthetic pathways. A consistent increase in the phosphatidylinositol species was observed in the vaccine candidate relative to its parental strain. This phenotype resulted in an increased production of phosphatidylinositol mannosides, a novel PhoP-regulated phenotype in the most widespread lineages of . This study represents a step ahead in our understanding of the MTBVAC vaccine, and some of the differential metabolites identified in this work might be used as potential vaccination biomarkers.
Topics: Bacterial Proteins; Biosynthetic Pathways; Chromatography, Liquid; Mass Spectrometry; Metabolomics; Mycobacterium tuberculosis; Phosphatidylinositols; Tuberculosis Vaccines
PubMed: 31099236
DOI: 10.1021/acsinfecdis.9b00008 -
Research in Microbiology 2003Mycobacterium tuberculosis expresses universal stress proteins (USPs) when its growth is retarded by oxygen depletion. This class of proteins is emerging as being... (Review)
Review
Mycobacterium tuberculosis expresses universal stress proteins (USPs) when its growth is retarded by oxygen depletion. This class of proteins is emerging as being important in the resistance of bacteria to stress and prolonged growth arrest. Here we assess the properties of USPs and their relevance to mycobacteria.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; Heat-Shock Proteins; Mycobacterium tuberculosis
PubMed: 12892844
DOI: 10.1016/S0923-2508(03)00081-0 -
Clinical Microbiology and Infection :... Jun 2011Mycobacterium tuberculosis harbours little DNA sequence diversity compared with other bacteria. However, there is mounting evidence that strain-to-strain variation in... (Review)
Review
Mycobacterium tuberculosis harbours little DNA sequence diversity compared with other bacteria. However, there is mounting evidence that strain-to-strain variation in this organism has been underestimated. We review our current understanding of the genetic diversity among M. tuberculosis clinical strains and discuss the relevance of this diversity for the ongoing global epidemics of drug-resistant tuberculosis. Based on findings in other bacteria, we propose that epistatic interactions between pre-existing differences in strain genetic background, acquired drug-resistance-conferring mutations and compensatory changes could play a role in the emergence and spread of drug-resistant M. tuberculosis.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Epistasis, Genetic; Evolution, Molecular; Genotype; Humans; Molecular Epidemiology; Mycobacterium tuberculosis; Polymorphism, Genetic; Tuberculosis
PubMed: 21682802
DOI: 10.1111/j.1469-0691.2011.03556.x