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Virulence Dec 2023(Mtb) is the causative agent of tuberculosis, an infectious disease with one of the highest morbidity and mortality rates worldwide. Leveraging its highly evolved... (Review)
Review
(Mtb) is the causative agent of tuberculosis, an infectious disease with one of the highest morbidity and mortality rates worldwide. Leveraging its highly evolved repertoire of non-protein and protein virulence factors, Mtb invades through the airway, subverts host immunity, establishes its survival niche, and ultimately escapes in the setting of active disease to initiate another round of infection in a naive host. In this review, we will provide a concise synopsis of the infectious life cycle of Mtb and its clinical and epidemiologic significance. We will also take stock of its virulence factors and pathogenic mechanisms that modulate host immunity and facilitate its spread. Developing a greater understanding of the interface between Mtb virulence factors and host defences will enable progress toward improved vaccines and therapeutics to prevent and treat tuberculosis.
Topics: Humans; Mycobacterium tuberculosis; Virulence; Tuberculosis; Virulence Factors; Host-Pathogen Interactions
PubMed: 36419223
DOI: 10.1080/21505594.2022.2150449 -
Cell Nov 2023Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse...
Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.
Topics: Animals; Mice; Biofilms; Lung; Mycobacterium tuberculosis; Tuberculosis; Virulence; Biomechanical Phenomena
PubMed: 37865090
DOI: 10.1016/j.cell.2023.09.016 -
Nature Aug 2023To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host. The mammalian cell entry (MCE)...
To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host. The mammalian cell entry (MCE) proteins are important virulence factors in M. tuberculosis, where they are encoded by large gene clusters and have been implicated in the transport of fatty acids and cholesterol across the impermeable mycobacterial cell envelope. Very little is known about how cargos are transported across this barrier, and it remains unclear how the approximately ten proteins encoded by a mycobacterial mce gene cluster assemble to transport cargo across the cell envelope. Here we report the cryo-electron microscopy (cryo-EM) structure of the endogenous Mce1 lipid-import machine of Mycobacterium smegmatis-a non-pathogenic relative of M. tuberculosis. The structure reveals how the proteins of the Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the cell envelope. The Mce1 complex is dominated by a curved, needle-like domain that appears to be unrelated to previously described protein structures, and creates a protected hydrophobic pathway for lipid transport across the periplasm. Our structural data revealed the presence of a subunit of the Mce1 complex, which we identified using a combination of cryo-EM and AlphaFold2, and name LucB. Our data lead to a structural model for Mce1-mediated lipid import across the mycobacterial cell envelope.
Topics: Animals; Bacterial Proteins; Cryoelectron Microscopy; Lipids; Membrane Transport Proteins; Mycobacterium tuberculosis; Tuberculosis; Virus Internalization; Virulence Factors; ATP-Binding Cassette Transporters; Periplasm; Protein Domains; Hydrophobic and Hydrophilic Interactions; Multiprotein Complexes
PubMed: 37495693
DOI: 10.1038/s41586-023-06366-0 -
Drug Discovery Today May 2024Tuberculosis (TB) presents a significant global health concern, with ∼10 million people developing TB and 1.3 million people dying from the disease each year. The... (Review)
Review
Tuberculosis (TB) presents a significant global health concern, with ∼10 million people developing TB and 1.3 million people dying from the disease each year. The standard treatment regimen for drug-susceptible TB was between 6 and 9 months until recently, presenting a prolonged therapeutic duration compared with other infectious diseases. This is a long time for patients to adhere to the medication, consequently increasing the risk of developing drug-resistant Mycobacterium tuberculosis - a significant challenge in TB management globally. Therefore, the primary objective of contemporary TB drug development research is to shorten the treatment duration. This review comprehensively explores the strategies aimed at shortening TB treatment.
Topics: Humans; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Drug Development; Tuberculosis, Multidrug-Resistant; Animals
PubMed: 38548262
DOI: 10.1016/j.drudis.2024.103955 -
Clinica Chimica Acta; International... Jun 2024One of predominant contributors to global mortality is tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (MTB). Inappropriate and ineffectual... (Review)
Review
One of predominant contributors to global mortality is tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (MTB). Inappropriate and ineffectual treatment can lead to the development of drug-resistant TB. One of the most common forms of drug-resistant TB is multidrug-resistant tuberculosis (MDR-TB), caused by mutations in the rpoB and katG genes that lead to resistance to anti-TB drugs, rifampicin (RIF) and isoniazid (INH), respectively. Although culturing remains the gold standard, it is not rapid thereby delaying potential treatment and potentially increasing the incidence of MDR-TB. In contrast, molecular techniques provide a highly sensitive and specific alternative. This review discusses the classification of biomarkers used to detect MDR-TB, some of the commonly used anti-TB drugs, and DNA mutations in MTB that lead to anti-TB resistance. The objective of this review is to increase awareness of the need for rapid and precise detection of MDR-TB cases to decrease morbidity and mortality of this infectious disease worldwide.
Topics: Tuberculosis, Multidrug-Resistant; Humans; Mycobacterium tuberculosis; Antitubercular Agents; Mutation
PubMed: 38697459
DOI: 10.1016/j.cca.2024.119701 -
Current Opinion in Ophthalmology Nov 2023To evaluate the epidemiology, microbiology, and pathology of Mycobacterium Tuberculosis (MTB). Utilizing these basic science concepts, the reader will discover how MTB... (Review)
Review
PURPOSE OF REVIEW
To evaluate the epidemiology, microbiology, and pathology of Mycobacterium Tuberculosis (MTB). Utilizing these basic science concepts, the reader will discover how MTB can cause disease in any part of ophthalmic system. This article will aid clinicians in establishing the difficult diagnosis and management strategies for ophthalmic tuberculosis (OTB).
RECENT FINDINGS
Recently, expert panels have reached a consensus on naming conventions and treatment strategies for the variety of ocular tuberculosis (TB). This consensus helps individual clinicians decide when to recommend full anti-TB treatment.
SUMMARY
Globally, TB is nearly ubiquitous in the human population. It is most recognized for its pulmonary disease, but pathology of nearly every structure of the ophthalmic system has been identified. This heterogeneity makes establishing a diagnosis difficult, but recent improvements in expert panel naming consensus and nucleic acid amplification tests are improving diagnostic abilities. Clinicians are now feeling more confident with prescribing anti-TB regimens, but ongoing questions regarding the use of oral steroids and risk of medication-induced ocular toxicity remain.
Topics: Humans; Tuberculosis; Mycobacterium tuberculosis
PubMed: 37593994
DOI: 10.1097/ICU.0000000000000991 -
FEMS Microbiology Reviews Mar 2024Tuberculosis (TB) remains one of the deadliest infectious diseases in human history, prevailing even in the 21st century. The causative agents of TB are represented by a... (Review)
Review
Tuberculosis (TB) remains one of the deadliest infectious diseases in human history, prevailing even in the 21st century. The causative agents of TB are represented by a group of closely related bacteria belonging to the Mycobacterium tuberculosis complex (MTBC), which can be subdivided into several lineages of human- and animal-adapted strains, thought to have shared a last common ancestor emerged by clonal expansion from a pool of recombinogenic Mycobacterium canettii-like tubercle bacilli. A better understanding of how MTBC populations evolved from less virulent mycobacteria may allow for discovering improved TB control strategies and future epidemiologic trends. In this review, we highlight new insights into the evolution of mycobacteria at the genus level, describing different milestones in the evolution of mycobacteria, with a focus on the genomic events that have likely enabled the emergence and the dominance of the MTBC. We also review the recent literature describing the various MTBC lineages and highlight their particularities and differences with a focus on host preferences and geographic distribution. Finally, we discuss on putative mechanisms driving the evolution of tubercle bacilli and mycobacteria in general, by taking the mycobacteria-specific distributive conjugal transfer as an example.
Topics: Animals; Humans; Mycobacterium tuberculosis; Bacillus; Genomics
PubMed: 38365982
DOI: 10.1093/femsre/fuae006 -
ELife Jul 2023The simultaneous delivery of protein and lipid antigens via nanoparticles may help efforts to develop a new vaccine for tuberculosis.
The simultaneous delivery of protein and lipid antigens via nanoparticles may help efforts to develop a new vaccine for tuberculosis.
Topics: Humans; Mycobacterium tuberculosis; Mycolic Acids; Tuberculosis; Antigens; Vaccines; Antigens, Bacterial
PubMed: 37477291
DOI: 10.7554/eLife.90407 -
Nature Microbiology Sep 2023
Topics: Humans; Mycobacterium tuberculosis; Educational Personnel
PubMed: 37587200
DOI: 10.1038/s41564-023-01454-3 -
Frontiers in Cellular and Infection... 2023Tuberculosis (TB) is a widespread infectious disease caused by (), which has been a significant burden for a long time. Post-translational modifications (PTMs) are... (Review)
Review
Tuberculosis (TB) is a widespread infectious disease caused by (), which has been a significant burden for a long time. Post-translational modifications (PTMs) are essential for protein function in both eukaryotic and prokaryotic cells. This review focuses on the contribution of protein acetylation to the function of and its infected macrophages. The acetylation of proteins plays a critical role in virulence, drug resistance, regulation of metabolism, and host anti-TB immune response. Similarly, the PTMs of host proteins induced by are crucial for the development, treatment, and prevention of diseases. Host protein acetylation induced by is significant in regulating host immunity against TB, which substantially affects the disease's development. The review summarizes the functions and mechanisms of acetyltransferase in virulence and drug resistance. It also discusses the role and mechanism of in regulating host protein acetylation and immune response regulation. Furthermore, the current scenario of isoniazid usage in therapy treatment is examined. Overall, this review provides valuable information that can serve as a preliminary basis for studying pathogenic research, developing new drugs, exploring in-depth drug resistance mechanisms, and providing precise treatment for TB.
Topics: Humans; Acetylation; Acetyltransferases; Mycobacterium tuberculosis; Protein Processing, Post-Translational; Tuberculosis; Macrophages
PubMed: 37560320
DOI: 10.3389/fcimb.2023.1218583