-
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 -
Cell Host & Microbe Nov 2023Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that...
Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated activation of the IFN-β pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.
Topics: Mycobacterium tuberculosis; Urease; Interferon-beta; Interferon Type I; Macrophages; Nucleotidyltransferases
PubMed: 37848028
DOI: 10.1016/j.chom.2023.09.010 -
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 -
Molecular Microbiology Aug 2023Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid... (Review)
Review
Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid acquisition of genomic data and the (much slower) confirmation of inferred genetic function threatens to widen unless techniques for fast, high-throughput functional validation can be applied at scale. This applies equally to Mycobacterium tuberculosis, the leading infectious cause of death globally and a pathogen whose genome, despite being among the first to be sequenced two decades ago, still contains many genes of unknown function. Here, we summarize the evolution of bacterial high-throughput functional genomics, focusing primarily on transposon (Tn)-based mutagenesis and the construction of arrayed mutant libraries in diverse bacterial systems. We also consider the contributions of CRISPR interference as a transformative technique for probing bacterial gene function at scale. Throughout, we situate our analysis within the context of functional genomics of mycobacteria, focusing specifically on the potential to yield insights into M. tuberculosis pathogenicity and vulnerabilities for new drug and regimen development. Finally, we offer suggestions for future approaches that might be usefully applied in elucidating the complex cellular biology of this major human pathogen.
Topics: Humans; DNA Transposable Elements; Genomics; Mutagenesis; Mycobacterium tuberculosis; Phenotype; Genome, Bacterial; High-Throughput Nucleotide Sequencing
PubMed: 37278255
DOI: 10.1111/mmi.15103 -
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 -
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 -
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 -
Cells Aug 2023Infectious diseases, particularly Tuberculosis (TB) caused by , pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most... (Review)
Review
Infectious diseases, particularly Tuberculosis (TB) caused by , pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.
Topics: Humans; Communicable Diseases; Biological Therapy; Mycobacterium tuberculosis; Drug Delivery Systems; Oligonucleotides, Antisense; RNA, Messenger
PubMed: 37626929
DOI: 10.3390/cells12162119