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Science Signaling Dec 2023A virulence factor promotes foam cell formation by inhibiting DNA repair.
A virulence factor promotes foam cell formation by inhibiting DNA repair.
Topics: Mycobacterium tuberculosis; DNA Repair
PubMed: 38113336
DOI: 10.1126/scisignal.adn5031 -
Gene Jan 2021Sequencing transposon mutant libraries have been pivotal in annotating essential and non-essential genes in bacteria. This is particularly very helpful in the case of...
Sequencing transposon mutant libraries have been pivotal in annotating essential and non-essential genes in bacteria. This is particularly very helpful in the case of Mycobacterium tuberculosis with a large part of its genome without known function. It is not known whether there are any variations in the essentiality states as a function of optimal growth in the absence of any selection pressure. We here grow a high-density mutant library of M. tuberculosis through serial cultures and monitor the temporal fluctuations in insertion frequencies across all TA dinucleotides in the genome. Genes that cause morphological and physiological heterogeneity or enable metabolic bypass were found to gradually lose insertions, while genes comprising the toxin-antitoxin systems were found to get enriched with insertions during growth in nutrient replete conditions. High levels of fluctuations were observed in genes involved in cell wall and cell processes, intermediary metabolism, and genes involved in virulence, suggesting new modes of adaptation undertaken by the mutants. We also report the essentiality status of several newly annotated genetic features.
Topics: DNA Transposable Elements; Gene Library; Genes, Essential; High-Throughput Nucleotide Sequencing; Humans; Mutagenesis, Insertional; Mycobacterium tuberculosis; Toxin-Antitoxin Systems; Virulence
PubMed: 32898604
DOI: 10.1016/j.gene.2020.145091 -
MSphere Aug 2021Autophagy is a fundamental cellular process that has important roles in innate and adaptive immunity against a broad range of microbes. Many pathogenic microbes have...
Autophagy is a fundamental cellular process that has important roles in innate and adaptive immunity against a broad range of microbes. Many pathogenic microbes have evolved mechanisms to evade or exploit autophagy. It has been previously demonstrated that induction of autophagy can suppress the intracellular survival of mycobacteria, and several PE_PGRS family proteins of Mycobacterium tuberculosis have been proposed to act as inhibitors of autophagy to promote mycobacterial survival. However, the mechanisms by which these effectors inhibit autophagy have not been defined. Here, we report detailed studies of M. tuberculosis deletion mutants of two genes, and , that we previously reported as having a role in preventing autophagy of infected host cells. These mutants resulted in increased autophagy and reduced intracellular survival of M. tuberculosis in macrophages. This phenotype was accompanied by increased cytokine production and antigen presentation by infected cells. We further demonstrated that autophagy inhibition by PE_PGRS20 and PE_PGRS47 resulted from canonical autophagy rather than autophagy flux inhibition. Using macrophages transfected to express PE_PGRS20 or PE_PGRS47, we showed that these proteins inhibited autophagy initiation directly by interacting with Ras-related protein Rab1A. Silencing of Rab1A in mammalian cells rescued the survival defects of the and deletion mutant strains and reduced cytokine secretion. To our knowledge, this is the first study to identify mycobacterial effectors that directly interact with host proteins responsible for autophagy initiation. Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which then resides and replicates mainly within host phagocytic cells. Autophagy is a complex host cellular process that helps control intracellular infections and enhance innate and adaptive immune responses. During coevolution with humans, M. tuberculosis has acquired various mechanisms to inhibit host cellular processes, including autophagy. We identified two related M. tuberculosis proteins, PE_PGRS20 and PE_PGRS47, as the first reported examples of specific mycobacterial effectors interfering with the initiation stage of autophagy. Autophagy regulation by these PE_PGRS proteins leads to increased bacterial survival in phagocytic cells and increased autophagic degradation of mycobacterial antigens to stimulate adaptive immune responses. A better understanding of how M. tuberculosis regulates autophagy in host cells could facilitate the design of new and more effective therapeutics or vaccines against tuberculosis.
Topics: Animals; Antigen Presentation; Autophagy; Bacterial Proteins; Host-Pathogen Interactions; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; RAW 264.7 Cells; rab1 GTP-Binding Proteins
PubMed: 34346699
DOI: 10.1128/mSphere.00549-21 -
Human Molecular Genetics Apr 2021For centuries, the Mycobacterium tuberculosis complex (MTBC) has infected numerous populations, both human and non-human, causing symptomatic tuberculosis (TB) in some... (Review)
Review
For centuries, the Mycobacterium tuberculosis complex (MTBC) has infected numerous populations, both human and non-human, causing symptomatic tuberculosis (TB) in some hosts. Research investigating the MTBC and how it has evolved with its host over time is sparse and has not resulted in many significant findings. There are even fewer studies investigating adaptation of the human host susceptibility to TB and these have largely focused on genome-wide association and candidate gene association studies. However, results emanating from these association studies are rarely replicated and appear to be population specific. It is, therefore, necessary to relook at the approach taken to investigate the relationship between the MTBC and the human host. Understanding that the evolution of the pathogen is coupled to the evolution of the host might be the missing link needed to effectively investigate their relationship. We hypothesize that this knowledge will bolster future efforts in combating the disease.
Topics: Adaptation, Physiological; Animals; DNA; Genetics, Population; Genome-Wide Association Study; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33258469
DOI: 10.1093/hmg/ddaa254 -
Biotechnology & Genetic Engineering... Apr 2023(MTB) causes one of the ancient diseases, Tuberculosis, affects people around the globe and its severity can be understood by its classification as a second infectious... (Review)
Review
(MTB) causes one of the ancient diseases, Tuberculosis, affects people around the globe and its severity can be understood by its classification as a second infectious disease after COVID-19 and the 13th leading cause of death according to a WHO report. Despite having advanced diagnostic approaches and therapeutic strategies, unfortunately, TB is still spreading across the population due to the emergence of drug-resistance MTB and Latent TB infection (LTBI). We are seeking for effective approaches to overcome these hindrances and efficient treatment for this perilous disease. Therefore, there is an urgent need to develop drugs based on operative targeting of the bacterial system that could result in both efficient treatment and lesser emergence of MDR-TB. One such promising target could be the secretory systems and especially the Type 7 secretory system (T7SS-ESX) of which is crucial for the secretion of effector proteins as well as in establishing host-pathogen interactions of the tubercle bacilli. The five paralogous ESX systems (ESX-1 to EXS-5) have been observed by genome analysis of MTB, among which ESX-1 and ESX-5 are substantial for virulence and mediating host cellular inflammasome. The bacterium growth and virulence can be modulated by targeting the T7SS. In the present review, we demonstrate the current status of therapeutics against MTB and focus on the function and cruciality of T7SS along with other secretory systems as a promising therapeutic target against Tuberculosis.
Topics: Humans; Mycobacterium tuberculosis; Bacterial Proteins; Secretome; COVID-19; Tuberculosis
PubMed: 35613080
DOI: 10.1080/02648725.2022.2076031 -
Nature Microbiology Oct 2023The order Corynebacteriales includes major industrial and pathogenic Actinobacteria such as Corynebacterium glutamicum or Mycobacterium tuberculosis. These bacteria have...
The order Corynebacteriales includes major industrial and pathogenic Actinobacteria such as Corynebacterium glutamicum or Mycobacterium tuberculosis. These bacteria have multi-layered cell walls composed of the mycolyl-arabinogalactan-peptidoglycan complex and a polar growth mode, thus requiring tight coordination between the septal divisome, organized around the tubulin-like protein FtsZ, and the polar elongasome, assembled around the coiled-coil protein Wag31. Here, using C. glutamicum, we report the discovery of two divisome members: a gephyrin-like repurposed molybdotransferase (Glp) and its membrane receptor (GlpR). Our results show how cell cycle progression requires interplay between Glp/GlpR, FtsZ and Wag31, showcasing a crucial crosstalk between the divisome and elongasome machineries that might be targeted for anti-mycobacterial drug discovery. Further, our work reveals that Corynebacteriales have evolved a protein scaffold to control cell division and morphogenesis, similar to the gephyrin/GlyR system that mediates synaptic signalling in higher eukaryotes through network organization of membrane receptors and the microtubule cytoskeleton.
Topics: Eukaryota; Bacterial Proteins; Cell Division; Mycobacterium tuberculosis
PubMed: 37679597
DOI: 10.1038/s41564-023-01473-0 -
Lipids in Health and Disease Oct 2021Mycobacterium tuberculosis (Mtb), the main etiology of tuberculosis (TB), is predominantly an intracellular pathogen that has caused infection, disease and death in... (Review)
Review
Mycobacterium tuberculosis (Mtb), the main etiology of tuberculosis (TB), is predominantly an intracellular pathogen that has caused infection, disease and death in humans for centuries. Lipid droplets (LDs) are dynamic intracellular organelles that are found across the evolutionary tree of life. This review is an evaluation of the current state of knowledge regarding Mtb-LD formation and associated Mtb transcriptome directly from sputa.Based on the LD content, Mtb in sputum may be classified into three groups: LD positive, LD negative and LD borderline. However, the clinical and evolutionary importance of each state is not well elaborated. Mounting evidence supports the view that the presence of LD positive Mtb bacilli in sputum is a biomarker of slow growth, low energy state, towards lipid degradation, and drug tolerance. In Mtb, LD may serve as a source of chemical energy, scavenger of toxic compounds, prevent destruction of Mtb through autophagy, delay trafficking of lysosomes towards the phagosome, and contribute to Mtb persistence. It is suggest that LD is a key player in the induction of a spectrum of phenotypic and metabolic states of Mtb in the macrophage, granuloma and extracellular sputum microenvironment. Tuberculosis patients with high proportion of LD positive Mtb in pretreatment sputum was associated with higher rate of poor treatment outcome, indicating that LD may have a clinical application in predicting treatment outcome.The propensity for LD formation among Mtb lineages is largely unknown. The role of LD on Mtb transmission and disease phenotype (pulmonary TB vs extra-pulmonary TB) is not well understood. Thus, further studies are needed to understand the relationships between LD positivity and Mtb lineage, Mtb transmission and clinical types.
Topics: Host-Pathogen Interactions; Humans; Lipid Droplets; Macrophages; Mycobacterium tuberculosis; Sputum; Transcriptome; Treatment Outcome; Tuberculosis
PubMed: 34602073
DOI: 10.1186/s12944-021-01550-5 -
Molecules (Basel, Switzerland) Jul 2022(), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution...
(), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution combined with whole genome sequencing analysis was used identify novel drug targets and drug resistance genes in associated with its intracellular growth in human macrophages. We performed a genome analysis of 53 mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as and lead targets reported in novel anti-tuberculosis drug screenings such as , , and , we have discovered several unrecognized candidate drug targets including . The exploration of the chemical mutant genomes could help novel drug discovery and the structural biology of compounds and associated mechanisms of action relevant to tuberculosis treatment.
Topics: Antitubercular Agents; Bacterial Proteins; Humans; INDEL Mutation; Macrophages; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Tuberculosis
PubMed: 35889319
DOI: 10.3390/molecules27144446 -
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 -
Journal of Drug Targeting Mar 2021(), the causative agent of tuberculosis (TB), remains a formidable threat in mortality and morbidity worldwide. Ethambutol (EMB) is one of the first-line drugs regimens... (Review)
Review
(), the causative agent of tuberculosis (TB), remains a formidable threat in mortality and morbidity worldwide. Ethambutol (EMB) is one of the first-line drugs regimens for TB treatment. Arabinosyl transferases are established targets of EMB, which is involved in the biosynthesis of arabinogalactan (AG) and lipoarabinomannan (LAM). Mutations among operon are responsible for around 70% clinical EMB resistant . In this review, we summarised other potential factors associated with EMB resistance via analysing whole genome, proteome and transcriptome of exposed to EMB. This will help to design better diagnosis of EMB resistance.
Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Ethambutol; Genes, Bacterial; Humans; Mutation; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 33210572
DOI: 10.1080/1061186X.2020.1853733