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Trends in Microbiology Jun 2018In this infographic, the genetics, phylogeny, physiology, and pathogenesis mechanisms of Mycobacterium tuberculosis are shown. Mycobacterium tuberculosis is the...
In this infographic, the genetics, phylogeny, physiology, and pathogenesis mechanisms of Mycobacterium tuberculosis are shown. Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), the leading cause of death due to a single infectious agent, claiming 1.7 million lives in 2016. Of the deaths attributable to TB in 2016, 22% occurred in people coinfected with HIV, and close to 5% of the 10.4 million incident cases of this disease were resistant to at least two of the first-line TB drugs. In this infographic, we describe the fundamental features of the genetics, phylogeny, and physiology of this member of the phylum Actinobacteria, which is associated increasingly with drug resistance mediated by mutations and rearrangements in its single, circular chromosome. We also highlight the key pathogenesis mechanisms employed by this slow-growing, facultative intracellular bacterium, which include avoidance of host cell clearance by arrest of the normal macrophage maturation process.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Macrophages; Mycobacterium tuberculosis; Phylogeny; Tuberculosis
PubMed: 29580884
DOI: 10.1016/j.tim.2018.02.012 -
Microbiology Spectrum Jul 2019is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy... (Review)
Review
is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy and the widespread use of a neonatal anti-TB vaccine. For a professional pathogen, retains a surprisingly large proportion of the metabolic repertoire found in nonpathogenic mycobacteria with very different lifestyles. Moreover, evidence that additional functions were acquired during the early evolution of the complex suggests the organism has adapted (and augmented) the metabolic pathways of its environmental ancestor to persistence and propagation within its obligate human host. A better understanding of pathogenicity, however, requires the elucidation of metabolic functions under disease-relevant conditions, a challenge complicated by limited knowledge of the microenvironments occupied and nutrients accessed by bacilli during host infection, as well as the reliance in experimental mycobacteriology on a restricted number of experimental models with variable relevance to clinical disease. Here, we consider metabolism within the framework of an intimate host-pathogen coevolution. Focusing on recent advances in our understanding of mycobacterial metabolic function, we highlight unusual adaptations or departures from the better-characterized model intracellular pathogens. We also discuss the impact of these mycobacterial "innovations" on the susceptibility of to existing and experimental anti-TB drugs, as well as strategies for targeting metabolic pathways. Finally, we offer some perspectives on the key gaps in the current knowledge of fundamental mycobacterial metabolism and the lessons which might be learned from other systems.
Topics: Animals; Antitubercular Agents; Humans; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Tuberculosis; Virulence
PubMed: 31350832
DOI: 10.1128/microbiolspec.GPP3-0067-2019 -
Journal of Medical Microbiology Nov 2015Some species of the Mycobacterium tuberculosis complex (MTBC), particularly Mycobacterium tuberculosis, which causes human tuberculosis (TB), are the first cause of... (Review)
Review
Some species of the Mycobacterium tuberculosis complex (MTBC), particularly Mycobacterium tuberculosis, which causes human tuberculosis (TB), are the first cause of death linked to a single pathogen worldwide. In the last decades, evolutionary studies have much improved our knowledge on MTBC history and have highlighted its long co-evolution with humans. Its ability to remain latent in humans, the extraordinary proportion of asymptomatic carriers (one-third of the entire human population), the deadly epidemics and the observed increasing level of resistance to antibiotics are proof of its evolutionary success. Many MTBC molecular signatures show not only that these bacteria are a model of adaptation to humans but also that they have influenced human evolution. Owing to the unbalance between the number of asymptomatic carriers and the number of patients with active TB, some authors suggest that infection by MTBC could have a protective role against active TB disease and also against other pathologies. However, it would be inappropriate to consider these infectious pathogens as commensals or symbionts, given the level of morbidity and mortality caused by TB.
Topics: Animals; Biological Evolution; Humans; Mycobacterium tuberculosis; Phylogeny; Tuberculosis
PubMed: 26385049
DOI: 10.1099/jmm.0.000171 -
Nature Jun 1998Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the...
Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve our understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino-acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.
Topics: Chromosome Mapping; Chromosomes, Bacterial; Drug Resistance, Microbial; Genome, Bacterial; Humans; Lipid Metabolism; Molecular Sequence Data; Mycobacterium tuberculosis; Sequence Analysis, DNA; Tuberculosis
PubMed: 9634230
DOI: 10.1038/31159 -
Microbiology (Reading, England) May 2024(Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche - the macrophage.... (Review)
Review
(Mtb) senses and adapts to host environmental cues as part of its pathogenesis. One important cue sensed by Mtb is the acidic pH of its host niche - the macrophage. Acidic pH induces widespread transcriptional and metabolic remodelling in Mtb. These adaptations to acidic pH can lead Mtb to slow its growth and promote pathogenesis and antibiotic tolerance. Mutants defective in pH-dependent adaptations exhibit reduced virulence in macrophages and animal infection models, suggesting that chemically targeting these pH-dependent pathways may have therapeutic potential. In this review, we discuss mechanisms by which Mtb regulates its growth and metabolism at acidic pH. Additionally, we consider the therapeutic potential of disrupting pH-driven adaptations in Mtb and review the growing class of compounds that exhibit pH-dependent activity or target pathways important for adaptation to acidic pH.
Topics: Mycobacterium tuberculosis; Hydrogen-Ion Concentration; Adaptation, Physiological; Animals; Humans; Tuberculosis; Macrophages; Virulence; Gene Expression Regulation, Bacterial; Bacterial Proteins; Antitubercular Agents
PubMed: 38717801
DOI: 10.1099/mic.0.001458 -
Tuberculosis (Edinburgh, Scotland) Jul 2019The currently available methods are unable to directly detect dormant forms of Mycobacterium tuberculosis (Mtb) in vivo. The persistence of Mtb in the host body is... (Review)
Review
The currently available methods are unable to directly detect dormant forms of Mycobacterium tuberculosis (Mtb) in vivo. The persistence of Mtb in the host body is detectable only in an indirect manner via the immunological response to Mtb-specific antigens. It is commonly recognized that the pathogen prevalently exists in the human body in a latent stage. Additional research efforts focusing on the Mtb dormancy are needed for development of sterilizing drugs, which are necessary to control LTBI and stop TB epidemic. To this end, the in vitro models of Mtb dormancy may be useful. This review briefly describes the phenomenon of Mtb dormancy and its role in the context of tuberculosis as a persistent bacterial infection; then the article characterizes in details the in vitro methods used for modeling the Mtb dormancy in bacterial cultures.
Topics: Antibiotics, Antitubercular; Bacterial Physiological Phenomena; Cell Proliferation; Drug Tolerance; Gene Expression Regulation; Humans; Latent Tuberculosis; Models, Biological; Mycobacterium tuberculosis
PubMed: 31378272
DOI: 10.1016/j.tube.2019.05.005 -
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 -
Biological Chemistry Feb 2020Tuberculosis caused by Mycobacterium tuberculosis remains a serious threat to public health. The M. tuberculosis cell envelope is closely related to its virulence and... (Review)
Review
Tuberculosis caused by Mycobacterium tuberculosis remains a serious threat to public health. The M. tuberculosis cell envelope is closely related to its virulence and drug resistance. Mycobacterial membrane large proteins (MmpL) are lipid-transporting proteins of the efflux pump resistance nodulation cell division (RND) superfamily with lipid substrate specificity and non-transport lipid function. Mycobacterial membrane small proteins (MmpS) are small regulatory proteins, and they are also responsible for some virulence-related effects as accessory proteins of MmpL. The MmpL transporters are the candidate targets for the development of anti-tuberculosis drugs. This article summarizes the structure, function, phylogenetics of M. tuberculosis MmpL/S proteins and their roles in host immune response, inhibitors and regulatory system.
Topics: Antitubercular Agents; Membrane Transport Proteins; Microbial Sensitivity Tests; Mycobacterium tuberculosis
PubMed: 31652116
DOI: 10.1515/hsz-2019-0326 -
Tuberculosis (Edinburgh, Scotland) Nov 2011The diverse clinico- and histopathological features, frequency of transmission and treatment outcome of Mycobacterium tuberculosis have been associated with several... (Review)
Review
The diverse clinico- and histopathological features, frequency of transmission and treatment outcome of Mycobacterium tuberculosis have been associated with several environmental, host and bacterial factors. Many Mycobacterium tuberculosis genotypes have been studied in an attempt to understand the genetic variations among the different genotypes and to clarify their contribution to phenotypic differences. Strains of the Beijing genotype have been extensively investigated due to their increased ability to spread and cause disease. Here we review the evidence of hypervirulence of the Beijing genotype as well as other Beijing-associated phenotypic characteristics such as alternate host immune modulation, clinical and pathological features, drug resistance, resistance to BCG vaccination and other epidemiological features to enhance our understanding of the contribution of pathogenic factors. From the data collected it is clear that the genetic background of Mycobacterium tuberculosis may influence the differential induction of the immune response, drug resistance patterns and clinical, epidemiological and pathogenic features which define disease progression following infection. This highlights the importance of ongoing research into the genetic mechanisms underlying the phenotypic and genotypic characteristics of different Mycobacterium tuberculosis genotype strains. Furthermore, these findings could help to direct future drug, vaccine and diagnostic test development towards targeting critical virulence factors and to identify persons at risk for developing active disease thereby limiting transmission and the perpetuation of the tuberculosis epidemic.
Topics: Bacterial Typing Techniques; Genetic Variation; Genotype; Humans; Mycobacterium tuberculosis; Phenotype; Tuberculosis
PubMed: 21835699
DOI: 10.1016/j.tube.2011.07.005 -
BioMed Research International 2014Tuberculosis (TB) has been the biggest killer in the human history; currently, Mycobacterium tuberculosis (Mtb) kills nearly 2 million people each year worldwide. The... (Review)
Review
Tuberculosis (TB) has been the biggest killer in the human history; currently, Mycobacterium tuberculosis (Mtb) kills nearly 2 million people each year worldwide. The high prevalence of TB obligates the identification of new therapeutic targets and the development of anti-TB vaccines that can control multidrug resistance and latent TB infections. Membrane proteins have recently been suggested as key targets for bacterial viability. Current studies have shown that mycobacteria P-type ATPases may play critical roles in ion homeostasis and in the response of mycobacteria to toxic substances in the intraphagosomal environment. In this review, we bring together the genomic, transcriptomic, and structural aspects of the P-type ATPases that are relevant during active and latent Mtb infections, which can be useful in determining the potential of these ATPases as drug targets and in uncovering their possible roles in the development of new anti-TB attenuated vaccines.
Topics: Adenosine Triphosphatases; Antitubercular Agents; Drug Discovery; Humans; Molecular Targeted Therapy; Mycobacterium tuberculosis; Tuberculosis Vaccines
PubMed: 25110669
DOI: 10.1155/2014/296986