-
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 -
Frontiers in Immunology 2020Tuberculosis (TB) is a leading cause of death worldwide following infection with (Mtb), with 1.5 million deaths from this disease reported in 2018. Once the bacilli are... (Review)
Review
Tuberculosis (TB) is a leading cause of death worldwide following infection with (Mtb), with 1.5 million deaths from this disease reported in 2018. Once the bacilli are inhaled, alveolar and interstitial macrophages become infected with Mtb and differentiate into lipid-laden foamy macrophages leading to lung inflammation. Thus, the presence of lipid-laden foamy macrophages is the hallmark of TB granuloma; these Mtb-infected foamy macrophages are the major niche for Mtb survival. The fate of TB pathogenesis is likely determined by the altered function of Mtb-infected macrophages, which initiate and mediate TB-related lung inflammation. As Mtb-infected foamy macrophages play central roles in the pathogenesis of Mtb, they may be important in the development of host-directed therapy against TB. Here, we summarize and discuss the current understanding of the alterations in alveolar and interstitial macrophages in the regulation of Mtb infection-induced immune responses. Metabolic reprogramming of lipid-laden foamy macrophages following Mtb infection or virulence factors are also summarized. Furthermore, we review the therapeutic interventions targeting immune responses and metabolic pathways, from , and clinical studies. This review will further our understanding of the Mtb-infected foamy macrophages, which are both the major Mtb niche and therapeutic targets against TB.
Topics: Animals; Cellular Reprogramming; Foam Cells; Host-Pathogen Interactions; Humans; Inflammation; Macrophages, Alveolar; Mice; Mycobacterium tuberculosis; Tuberculosis
PubMed: 32477367
DOI: 10.3389/fimmu.2020.00910 -
Frontiers in Cellular and Infection... 2022exhibits a remarkable ability to interfere with the host antimicrobial response. The pathogen exploits elaborate strategies to cope with diverse host-induced stressors... (Review)
Review
exhibits a remarkable ability to interfere with the host antimicrobial response. The pathogen exploits elaborate strategies to cope with diverse host-induced stressors by modulating its metabolism and physiological state to prolong survival and promote persistence in host tissues. Elucidating the adaptive strategies that employs during infection to enhance persistence is crucial to understanding how varying physiological states may differentially drive disease progression for effective management of these populations. To improve our understanding of the phenotypic adaptation of , we review the adaptive strategies employed by to sense and coordinate a physiological response following exposure to various host-associated stressors. We further highlight the use of animal models that can be exploited to replicate and investigate different aspects of the human response to infection, to elucidate the impact of the host environment and bacterial adaptive strategies contributing to the recalcitrance of infection.
Topics: Animals; Anti-Bacterial Agents; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis, Lymph Node
PubMed: 36237425
DOI: 10.3389/fcimb.2022.956607 -
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 -
Genomics, Proteomics & Bioinformatics Dec 2022Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), which is still the leading cause of mortality from a single infectious disease worldwide. The...
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), which is still the leading cause of mortality from a single infectious disease worldwide. The development of novel anti-TB drugs and vaccines is severely hampered by the complicated and time-consuming genetic manipulation techniques for M. tuberculosis. Here, we harnessed an endogenous type III-A CRISPR/Cas10 system of M. tuberculosis for efficient gene editing and RNA interference (RNAi). This simple and easy method only needs to transform a single mini-CRISPR array plasmid, thus avoiding the introduction of exogenous protein and minimizing proteotoxicity. We demonstrated that M. tuberculosis genes can be efficiently and specifically knocked in/out by this system as confirmed by DNA high-throughput sequencing. This system was further applied to single- and multiple-gene RNAi. Moreover, we successfully performed genome-wide RNAi screening to identify M. tuberculosis genes regulating in vitro and intracellular growth. This system can be extensively used for exploring the functional genomics of M. tuberculosis and facilitate the development of novel anti-TB drugs and vaccines.
Topics: Humans; Mycobacterium tuberculosis; Gene Editing; RNA Interference; Tuberculosis; Antitubercular Agents; CRISPR-Cas Systems
PubMed: 34923124
DOI: 10.1016/j.gpb.2021.01.008 -
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 -
EBioMedicine Mar 2020Mycobacterium tuberculosis (M.tb) is likely the most successful human pathogen, capable of evading protective host immune responses and driving metabolic changes to... (Review)
Review
Mycobacterium tuberculosis (M.tb) is likely the most successful human pathogen, capable of evading protective host immune responses and driving metabolic changes to support its own survival and growth. Ineffective innate and adaptive immune responses inhibit effective clearance of the bacteria from the human host, resulting in the progression to active TB disease. Many regulatory mechanisms exist to prevent immunopathology, however, chronic infections result in the overproduction of regulatory myeloid cells, like myeloid-derived suppressor cells (MDSC), which actively suppress protective host T lymphocyte responses among other immunosuppressive mechanisms. The mechanisms of M.tb internalization by MDSC and the involvement of host-derived lipid acquisition, have not been fully elucidated. Targeted research aimed at investigating MDSC impact on phagocytic control of M.tb, would be advantageous to our collective anti-TB arsenal. In this review we propose a mechanism by which M.tb may be internalized by MDSC and survive via the manipulation of host-derived lipid sources.
Topics: Animals; Caveolins; Humans; Immune Evasion; Immunity, Innate; Membrane Microdomains; Mycobacterium tuberculosis; Myeloid-Derived Suppressor Cells; Tuberculosis
PubMed: 32113158
DOI: 10.1016/j.ebiom.2020.102670 -
American Journal of Respiratory and... Jul 2022
Topics: Bacterial Proteins; Humans; Hypoxia; Inflammation; Mycobacterium tuberculosis; Virulence
PubMed: 35442854
DOI: 10.1164/rccm.202203-0432ED -
EBioMedicine Oct 2021
Topics: Host-Pathogen Interactions; Humans; Mycobacterium avium; Mycobacterium tuberculosis; Tuberculosis
PubMed: 34717837
DOI: 10.1016/j.ebiom.2021.103659 -
Microbiology (Reading, England) Mar 2021The success of as a pathogen is well established: tuberculosis is the leading cause of death by a single infectious agent worldwide. The threat of multi- and... (Review)
Review
The success of as a pathogen is well established: tuberculosis is the leading cause of death by a single infectious agent worldwide. The threat of multi- and extensively drug-resistant bacteria has renewed global concerns about this pathogen and understanding its virulence strategies will be essential in the fight against tuberculosis. The current review will focus on phthiocerol dimycocerosates (PDIMs), a long-known and well-studied group of complex lipids found in the cell envelope. Numerous studies show a role for PDIMs in several key steps of pathogenesis, with recent studies highlighting its involvement in bacterial virulence, in association with the ESX-1 secretion system. Yet, the mechanisms by which PDIMs help to control macrophage phagocytosis, inhibit phagosome acidification and modulate host innate immunity, remain to be fully elucidated.
Topics: Animals; Cell Membrane; Host-Pathogen Interactions; Humans; Lipids; Macrophages; Mycobacterium tuberculosis; Phagocytosis; Tuberculosis; Virulence
PubMed: 33629944
DOI: 10.1099/mic.0.001042