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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 -
Immunological Reviews Mar 2015The causative agent of human tuberculosis (TB), Mycobacterium tuberculosis, is an obligate pathogen that evolved to exclusively persist in human populations. For M.... (Review)
Review
The causative agent of human tuberculosis (TB), Mycobacterium tuberculosis, is an obligate pathogen that evolved to exclusively persist in human populations. For M. tuberculosis to transmit from person to person, it has to cause pulmonary disease. Therefore, M. tuberculosis virulence has likely been a significant determinant of the association between M. tuberculosis and humans. Indeed, the evolutionary success of some M. tuberculosis genotypes seems at least partially attributable to their increased virulence. The latter possibly evolved as a consequence of human demographic expansions. If co-evolution occurred, humans would have counteracted to minimize the deleterious effects of M. tuberculosis virulence. The fact that human resistance to infection has a strong genetic basis is a likely consequence of such a counter-response. The genetic architecture underlying human resistance to M. tuberculosis remains largely elusive. However, interactions between human genetic polymorphisms and M. tuberculosis genotypes have been reported. Such interactions are consistent with local adaptation and allow for a better understanding of protective immunity in TB. Future 'genome-to-genome' studies, in which locally associated human and M. tuberculosis genotypes are interrogated in conjunction, will help identify new protective antigens for the development of better TB vaccines.
Topics: Adaptation, Biological; Animals; Biological Evolution; Disease Susceptibility; Genetic Drift; Genome, Bacterial; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Phylogeny; Time Factors; Tuberculosis; Virulence
PubMed: 25703549
DOI: 10.1111/imr.12264 -
Microbiology Spectrum Mar 2017Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as Mycobacterium... (Review)
Review
Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as Mycobacterium tuberculosis that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environments. Comparative genomic analyses have established that chromosomal mutations enable M. tuberculosis to adapt to these stresses: the emergence of drug-resistant isolates provides direct evidence of this capacity, so too the well-documented genetic diversity among M. tuberculosis lineages across geographic loci, as well as the microvariation within individual patients that is increasingly observed as whole-genome sequencing methodologies are applied to clinical samples and tuberculosis (TB) disease models. However, the precise mutagenic mechanisms responsible for M. tuberculosis evolution and adaptation are poorly understood. Here, we summarize current knowledge of the machinery responsible for DNA replication in M. tuberculosis, and discuss the potential contribution of the expanded complement of mycobacterial DNA polymerases to mutagenesis. We also consider briefly the possible role of DNA replication-in particular, its regulation and coordination with cell division-in the ability of M. tuberculosis to withstand antibacterial stresses, including host immune effectors and antibiotics, through the generation at the population level of a tolerant state, or through the formation of a subpopulation of persister bacilli-both of which might be relevant to the emergence and fixation of genetic drug resistance.
Topics: Adaptation, Biological; Animals; DNA Replication; Humans; Mutation; Mycobacterium tuberculosis
PubMed: 28361736
DOI: 10.1128/microbiolspec.TBTB2-0027-2016 -
IUBMB Life Sep 2018More than a century has passed since the identification of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB), we still are nowhere close to... (Review)
Review
More than a century has passed since the identification of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB), we still are nowhere close to eradicating this deadly disease. Moreover, emergence of new drug-resistant strains has further complicated the situation, making it even more difficult to treat by conventional therapy regimens. Humans are the only reservoir for the existence and propagation of Mtb, which suggests that its latent forms will be most difficult to eradicate, till the human race lasts. Mtb has been associated with us for ages and its evolution is strictly guided to exploit its human host for survival and spread. The strategies employed by Mtb are unique and host specific, thereby making it hard to break this association without accurate understanding of this host-pathogen interaction. Metabolic pathways have always been at the heart of Mtb pathogenesis, with a continuous cross-talk between the pathogen and the host. Over the years, Mtb has mastered the art of manipulating the host machinery, along with modulating its own metabolism for survival in the hostile conditions. Here we aim to summarize the history of tuberculosis, its pathology and recent advances in basic understanding of the machinery, with eventual gape on the novel therapeutic strategies emerged in the past decade. © 2018 IUBMB Life, 70(9):917-925, 2018.
Topics: Animals; Antitubercular Agents; Drug Design; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 30129097
DOI: 10.1002/iub.1882 -
Advances in Experimental Medicine and... 2017Genome-based insights into the evolution of Mycobacterium tuberculosis and other tuberculosis-causing mycobacteria are constantly increasing. In particular, the recent... (Review)
Review
Genome-based insights into the evolution of Mycobacterium tuberculosis and other tuberculosis-causing mycobacteria are constantly increasing. In particular, the recent genomic and functional characterization of several Myocbacterium canettii strains, which are thought to resemble in many aspects the putative common ancestor of the members of the M. tuberculosis complex (MTBC), has consolidated a plausible scenario of the early evolution of tuberculosis-causing mycobacteria, in which the clonal MTBC, comprising numerous key pathogens of mammalian hosts, has evolved from a generalist mycobacterium living in the environment. These studies also have considerably enriched our knowledge on selected molecular events that likely have contributed to the incursion, maintenance and spread of the MTBC members in diverse mammalian hosts. Here, we summarize and discuss recently revealed molecular and evolutionary aspects and emphasize the vast utility of M. canettii strains for identifying the mechanisms that contributed to the global emergence of M. tuberculosis as one of the most important human pathogens.
Topics: Animals; Biological Evolution; Genome, Bacterial; Humans; Mycobacterium; Mycobacterium Infections; Mycobacterium tuberculosis; Phylogeny; Phylogeography; Virulence
PubMed: 29116628
DOI: 10.1007/978-3-319-64371-7_2 -
ACS Infectious Diseases Mar 2023() lacking functional homoserine transacetylase (HTA) is compromised in methionine biosynthesis, protein synthesis, and in the activity of multiple essential...
() lacking functional homoserine transacetylase (HTA) is compromised in methionine biosynthesis, protein synthesis, and in the activity of multiple essential -adenosyl-l-methionine-dependent enzymes. Additionally, deficient mutants are further disarmed by the toxic accumulation of lysine due to a redirection of the metabolic flux toward the lysine biosynthetic pathway. Studies with deletion mutants and crystallographic studies of the apoenzyme have, respectively, validated HTA as an essential enzyme and revealed a ligandable binding site. Seeking a mechanistic characterization of this enzyme, we report crucial structural details and comprehensive functional characterization of HTA. Crystallographic and mass spectral observation of the acetylated HTA intermediate and initial velocity studies were consistent with a ping-pong kinetic mechanism. Wild-type HTA and its site-directed mutants were kinetically characterized with a panel of natural and alternative substrates to understand substrate specificity and identify critical residues for catalysis. Titration experiments using fluorescence quenching showed that both substrates─acetyl-CoA and l-homoserine─engage in a strong and weak binding interaction with HTA. Additionally, substrate inhibition by acetyl-CoA and product inhibition by CoA and -acetyl-l-homoserine were proposed to form the basis of a feedback regulation mechanism. By furnishing key mechanistic and structural information, these studies provide a foundation for structure-based design efforts around this attractive target.
Topics: Mycobacterium tuberculosis; Lysine; Acetyltransferases; Methionine; Acetyl Coenzyme A
PubMed: 36753622
DOI: 10.1021/acsinfecdis.2c00541 -
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 -
Microbiology (Reading, England) Sep 2014Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a... (Review)
Review
Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a process vital to the host's defence against infection. Adhesins are microbial cell surface molecules or structures that mediate the attachment of the microbe to host cells and thus the host-pathogen interaction. They also play a crucial role in bacterial aggregation and biofilm formation. In this review, we discuss the role of adhesins in the pathogenesis of the aetiological agent of tuberculosis, Mycobacterium tuberculosis. We also provide insight into the structure and characteristics of some of the characterized and putative M. tuberculosis adhesins. Finally, we examine the potential of adhesins as targets for the development of tuberculosis control strategies.
Topics: Adhesins, Bacterial; Antitubercular Agents; Biomarkers; Diagnostic Tests, Routine; Mycobacterium tuberculosis; Virulence Factors
PubMed: 25009234
DOI: 10.1099/mic.0.082206-0 -
Current Topics in Microbiology and... 2016Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb) and represents one of the most relevant bacterial diseases worldwide. Recent advances have... (Review)
Review
Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb) and represents one of the most relevant bacterial diseases worldwide. Recent advances have yielded new insights into the molecular basis of the immune response required for restriction of the pathogen and also highlighted determinants of immunopathology in TB. Several innate immune mediators including soluble proteins as well as lipid molecules participate in both processes, and their mechanisms of action during TB have been extensively studies over the past years. Among those mediators, inflammasomes are essential signaling platforms that execute crucial functions in several areas of immunology and beyond. This chapter aims to summarize what is known about the roles of the inflammasome during infection with Mtb from both in vitro studies as well as from in vivo work. A better understanding of the complex interactions between Mtb and the host immune system could reveal novel therapeutic approaches and improve current vaccination protocols in TB.
Topics: Animals; Host-Pathogen Interactions; Humans; Immunity, Innate; Inflammasomes; Mycobacterium tuberculosis; Tuberculosis
PubMed: 27460810
DOI: 10.1007/978-3-319-41171-2_9 -
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