Featured
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| Open AccessDynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy
Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen.
- Maxime Mistretta
- , Mena Cimino
- & Giulia Manina
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Article
| Open AccessSputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis
In patients with drug-resistant tuberculosis who receive treatment with new and repurposed drugs, indicators of advanced disease and delayed conversion were associated with an increased risk of reversion. These factors may be targets for close monitoring.
- Sooyeon Kho
- , Kwonjune J. Seung
- & Molly Franke
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| Open AccessThe recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova
Chitwood et al. report on the rapid expansion of a Ural-lineage multidrug resistant strain of Mycobacterium tuberculosis in Moldova. This strain has an estimated reproduction number more than two times greater than otherwise similar drug susceptible strains.
- Melanie H. Chitwood
- , Caroline Colijn
- & Benjamin Sobkowiak
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| Open AccessTcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection
Stupar et al. describe a new role for the Mycobacterium tuberculosis two-component system, TcrXY, in the modulation of up to 70 genes, including two effectors, TarA and TarB which mitigate intracellular redox stress.
- Miljan Stupar
- , Lendl Tan
- & Nicholas P. West
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Q&A
| Open AccessA spotlight on the tuberculosis epidemic in South Africa
Tuberculosis is the leading cause of death from a single infectious agent, with over 25% of these occurring in the African region. Multi-drug resistant strains which do not respond to first-line antibiotics continue to emerge, putting at risk numerous public health strategies which aim to reduce incidence and mortality. Here, we speak with Professor Valerie Mizrahi, world-leading researcher and former director of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, regarding the tuberculosis burden in South Africa. We discuss the challenges faced by researchers, the lessons that need to be learnt and current innovations to better understand the overall response required to accelerate progress.
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| Open AccessIdentification of differentially recognized T cell epitopes in the spectrum of tuberculosis infection
T cells play critical roles in the immune pathology of tuberculosis. Here the authors perform a proteome-wide screen of T cell antigens and reactivity to mycobacterium tuberculosis at different stages of infection.
- Sudhasini Panda
- , Jeffrey Morgan
- & Cecilia S. Lindestam Arlehamn
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| Open AccessRecently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy
Marking of recently activated T cells may help further our understanding of immunity against Mycobacterium tuberculosis (Mtb). Here the authors use Nur77-GFP reporter mice infected with Mtb and systems data approaches to implicate OX40 as a marker for recently activated, functionally and transcriptome-wise distinct CD4 T cells, and as a potential target for immunotherapy.
- Abigail R. Gress
- , Christine E. Ronayne
- & Tyler D. Bold
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Article
| Open AccessInhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide
The mode of action of the tuberculosis antibiotic pyrazinamide is poorly understood. Here, Krug et al show that pyrazinamide inhibits the immune regulator PARP1 and demonstrate PARP1 inhibition as a host-directed therapy.
- Stefanie Krug
- , Manish Gupta
- & William R. Bishai
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Article
| Open AccessGlobal burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis
Rifampicin-resistant tuberculosis (RR-TB) requires longer, more toxic therapy than rifampicin-sensitive disease and is associated with a higher occurrence of long-term sequelae. In this mathematical modeling study, the authors estimate that incident RR-TB in 2020 will be responsible for ~6.9 million disability-adjusted life years; 44% due to post-tuberculosis sequelae.
- Nicolas A. Menzies
- , Brian W. Allwood
- & Ted Cohen
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Article
| Open AccessGlycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes
Patients with diabetes mellitus have an increased risk of developing tuberculosis. Here the authors show that increased blood levels of glycerol in mice with type 2 diabetes contributes to their susceptibility to infection, as glycerol is one of the main carbon sources for the bacteria.
- Nuria Martinez
- , Lorissa J. Smulan
- & Hardy Kornfeld
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Article
| Open AccessNAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis
Mycobacterium tuberculosis disrupts glycolysis in infected myeloid cells. Here, Pacl et al. show that maximal glycolytic capacity in myeloid cells is essential for host protection from tuberculosis and that NAD(H) homeostasis underlies glycolysis-mediated protection of the host.
- Hayden T. Pacl
- , Krishna C. Chinta
- & Adrie J. C. Steyn
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Article
| Open AccessAddressing mechanism bias in model-based impact forecasts of new tuberculosis vaccines
The complex transmission chain of tuberculosis (TB) forces mathematical modelers to make mechanistic assumptions when modelling vaccine effects. Here, authors posit a Bayesian formalism that unlocks mechanism-agnostic impact forecasts for TB vaccines.
- M. Tovar
- , Y. Moreno
- & J. Sanz
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Article
| Open AccessStructural insights into RNase J that plays an essential role in Mycobacterium tuberculosis RNA metabolism
Here the authors report the crystal structures of RNase J from Mycobacterium tuberculosis in apo-state and complex with single strand RNA, revealing its physiological function in RNA metabolism.
- Luyao Bao
- , Juan Hu
- & Jixi Li
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Article
| Open AccessTransmission modeling to infer tuberculosis incidence prevalence and mortality in settings with generalized HIV epidemics
Accurately estimating the burden of tuberculosis is challenging due to incomplete registration systems and the relationship with HIV. Here, the authors develop a Bayesian modelling strategy accounting for these factors that estimates age- and country-specific annual risks of infection and the proportion resulting from recent infection.
- Peter J. Dodd
- , Debebe Shaweno
- & Helen Ayles
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| Open AccessFerroptosis hijacking by Mycobacterium tuberculosis
A recent study from Nature Communications reveals that Mycobacterium tuberculosis can hijack epigenetic machinery in host cells and induce host cell ferroptosis, which promotes pathogen pathogenicity and spread. These findings also suggest new therapeutic strategies to treat tuberculosis.
- Boyi Gan
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| Open AccessA mycobacterial effector promotes ferroptosis-dependent pathogenicity and dissemination
Ferroptosis is an iron-dependent form of cell death whose role in infectious diseases is being elucidated. Here, Qiang et al. show that PtpA, an effector secreted by Mycobacterium tuberculosis, induces ferroptosis by hijacking host arginine methyltransferase PRMT6 to promote its pathogenicity and dissemination.
- Lihua Qiang
- , Yong Zhang
- & Jing Wang
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Article
| Open AccessSafety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults
Here the authors present results from a randomized, double-blinded Phase 1 clinical trial, testing a thermostable presentation of a clinical-stage adjuvanted subunit tuberculosis vaccine candidate. The vaccine candidate is safe and well tolerated, and elicits comparable or improved immune responses compared to the non-thermostable presentation.
- Zachary K. Sagawa
- , Cristina Goman
- & Christopher B. Fox
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| Open AccessPhylogeography and transmission of Mycobacterium tuberculosis spanning prisons and surrounding communities in Paraguay
To role that carceral institutions play in Mycobacterium tuberculosis transmission remains somewhat unknown. Authors perform a prospective genomic surveillance study, to assess transmission dynamics in prisons and surrounding communities in Paraguay.
- Gladys Estigarribia Sanabria
- , Guillermo Sequera
- & Katharine S. Walter
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| Open AccessDynamic 18F-Pretomanid PET imaging in animal models of TB meningitis and human studies
Pretomanid has been approved for use in cases of multi-drug resistant pulmonary tuberculosis, yet the penetration of this antibiotic into other target tissues is not well established. Authors provide insight on pretomanid pharmacokinetics in the central nervous system, using positron emission tomography in animal models, and human studies.
- Filipa Mota
- , Camilo A. Ruiz-Bedoya
- & Sanjay K. Jain
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| Open AccessInflammation and immune activation are associated with risk of Mycobacterium tuberculosis infection in BCG-vaccinated infants
The identification of immune correlates of protection in humans would inform on the design and development of tuberculosis vaccine candidates. In this work, authors examine samples collected from South African infants, to determine whether the correlates of risk of tuberculosis disease, previously identified in this population, are also correlates of risk of M. tuberculosis infection.
- Iman Satti
- , Rachel E. Wittenberg
- & Helen McShane
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| Open AccessLysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs
Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.
- Simon R. Green
- , Susan H. Davis
- & Laura A. T. Cleghorn
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Article
| Open AccessHIF-1 stabilization in T cells hampers the control of Mycobacterium tuberculosis infection
The role of hypoxia inducible factors in infection and immune response is unclear. Here, the authors study their impact on the regulation of T cells responses during Mycobacteria tuberculosis infection using transcriptomics, flow cytometry and in vivo infection.
- Ruining Liu
- , Victoria Muliadi
- & Martin E. Rottenberg
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Article
| Open AccessTranscontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis
An outbreak of the multidrug-resistant Mycobacterium tuberculosis lineage W148 has spread widely across Russia, Central Asia and Europe. Here, the authors use whole genome sequences of ~700 isolates of this lineage collected over ~20 years to analyze its spread, evolution of drug resistance, and impact of compensatory mutations.
- Matthias Merker
- , Jean-Philippe Rasigade
- & Thierry Wirth
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| Open AccessA long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis
Non-adherence to anti-tubercular therapy Mycobacterium tuberculosis infection can lead to treatment failure and even the development of drug resistance. In this work, the authors develop a long-acting delivery system of the anti-tuberculosis drug rifabutin and assess translational potential in vivo.
- Manse Kim
- , Claire E. Johnson
- & Martina Kovarova
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| Open AccessSelf-evolving vision transformer for chest X-ray diagnosis through knowledge distillation
Although deep learning-based computer-aided diagnosis systems have recently achieved expert level performance, developing a robust model requires large, high-quality data with annotations. Here, the authors present a framework which can improve the performance of vision transformer simultaneously with self-supervision and self-training.
- Sangjoon Park
- , Gwanghyun Kim
- & Jong Chul Ye
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Article
| Open AccessViral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx
Viral coinfection alongside mycobacterium tuberculosis (Mtb) infection may lead to immune complications or interference with immune responses. Here the authors show that in mice infected with Mtb and LCMV virus the specific TH1 response to MTb is reduced through a type I IFN response to the infecting virus.
- Tae Gun Kang
- , Kee Woong Kwon
- & Sung Jae Shin
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Article
| Open AccessIntegrating central nervous system metagenomics and host response for diagnosis of tuberculosis meningitis and its mimics
Tuberculous meningitis is difficult to differentiate from meningitis caused by other pathogens. Here, the authors combine metagenomics-based pathogen detection in cerebrospinal fluid with a host gene expression-based machine learning classifier for diagnosis.
- P. S. Ramachandran
- , A. Ramesh
- & M. R. Wilson
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Article
| Open AccessGeographically dispersed zoonotic tuberculosis in pre-contact South American human populations
‘Pre-contact era humans from coastal South America were infected by Mycobacterium pinnipedii, most likely, through contact with infected pinnipeds. Here, the authors investigate the presence of M. pinnipedii in pre-contact era humans from inland South America and explore potential scenarios of human-to-human or animal-mediated transmission.’
- Åshild J. Vågene
- , Tanvi P. Honap
- & Kirsten I. Bos
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| Open AccessEarly alveolar macrophage response and IL-1R-dependent T cell priming determine transmissibility of Mycobacterium tuberculosis strains
Halting tuberculosis transmission is crucial to TB elimination. Here the authors implicate IL-1R dependent T cell priming as the underlying mechanism determining variability in transmission of Mycobacterium tuberculosis strains.
- Arianne Lovey
- , Sheetal Verma
- & Padmini Salgame
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Article
| Open AccessCost-effectiveness of routine adolescent vaccination with an M72/AS01E-like tuberculosis vaccine in South Africa and India
The M72/AS01E tuberculosis vaccine has shown 50% efficacy in preventing pulmonary TB disease in infected 18–50 year olds. Here, the authors demonstrate that, in most scenarios modelled, vaccination of adolescents would also be cost effective in two high incidence settings, South Africa and India.
- Rebecca C. Harris
- , Matthew Quaife
- & Richard G. White
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Article
| Open AccessCD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells
CD4 and CD8 co-receptors are routinely used to define distinct functional and phenotypic lineages of T cells. Here the authors show CD4 and CD8 also modulate the functional avidity of the CD1b-restricted response to mycobacterial lipid antigens
- Charlotte A. James
- , Yuexin Xu
- & Chetan Seshadri
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Article
| Open AccessGenomic signatures of pre-resistance in Mycobacterium tuberculosis
Signals of antimicrobial resistance in pathogen genomes may be detectable before the organism evolves an antimicrobial resistance phenotype. Here, the authors investigate this hypothesis using Mycobacterium tuberculosis data from Peru and identify candidate “pre-resistance” markers.
- Arturo Torres Ortiz
- , Jorge Coronel
- & Louis Grandjean
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Article
| Open AccessA Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients
Modulating the host immune response during tuberculosis is an emerging and critical advance in the therapeutic approach. Here the authors present data from a first-in-human phase I/II randomised trial on the safety and immunogenicity of adjuvant therapy of the H56:IC31 vaccine and cyclooxygenase-2 inhibitors in patients with tuberculosis.
- Synne Jenum
- , Kristian Tonby
- & Anne Ma Dyrhol-Riise
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| Open AccessA Mycobacterium tuberculosis-specific subunit vaccine that provides synergistic immunity upon co-administration with Bacillus Calmette-Guérin
Tuberculosis (TB) subunit vaccines have been investigated as boosters for BCG-induced immunity. Here, the authors design a TB subunit vaccine that doesn't share antigens with BCG and show that co-administration of the two vaccines broadens the T cell response to TB and increases protection.
- Joshua S. Woodworth
- , Helena Strand Clemmensen
- & Rasmus Mortensen
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| Open AccessMycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens
It is unclear why different antibiotics vary in their ability to shorten treatment of tuberculosis. Here, the authors show that a measure based on ribosomal RNA synthesis in Mycobacterium tuberculosis correlates with treatment shortening in culture, in mice and in human studies.
- Nicholas D. Walter
- , Sarah E. M. Born
- & Martin I. Voskuil
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| Open AccessGenomic analyses of Mycobacterium tuberculosis from human lung resections reveal a high frequency of polyclonal infections
Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. Here, Moreno-Molina et al. analyse sputum and surgical resections from tuberculosis patients, showing that the magnitude of polyclonal infections can be underestimated when only testing sputum samples.
- Miguel Moreno-Molina
- , Natalia Shubladze
- & Iñaki Comas
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Article
| Open AccessMonocyte progenitors give rise to multinucleated giant cells
Multinucleated giant cells characterize granuloma formation in mycobacterial infections. Here the authors identify monocyte precursors with distinct immunological and metabolic properties as a source of the granuloma multinucleated giant cell compartment.
- Anne Kathrin Lösslein
- , Florens Lohrmann
- & Philipp Henneke
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Article
| Open AccessGastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis
Antibiotic therapy can lead to pathogen clearance, but also to alterations in the gut microbiota and systemic immune responses. Here, the authors analyze data from patients with tuberculosis and healthy subjects to show that pathogen clearance and gut microbiota alterations are independently associated with antibiotic-induced changes of the inflammatory response of active tuberculosis.
- Matthew F. Wipperman
- , Shakti K. Bhattarai
- & Vanni Bucci
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Article
| Open AccessHuman antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis
Antibody responses against Mycobacteria infection have been reported, but whether and how they impact anti-bacteria immunity in the host is unclear. Here the authors characterize human anti-Mycobacteria antibodies to find them targeting a Mycobacteria transporter protein, PstS1, show distinct interaction modes in crystal structure, and mediate protection in vitro.
- Avia Watson
- , Hao Li
- & Natalia T. Freund
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Article
| Open AccessModelling the global burden of drug-resistant tuberculosis avertable by a post-exposure vaccine
Vaccines preventing tuberculosis disease progression have shown promising results in recent trials. Here, the authors use mathematical modelling to estimate that this type of vaccine could avert 10% of cases of rifampicin-resistant tuberculosis and 7% of deaths from 2020-2035.
- Han Fu
- , Joseph A. Lewnard
- & Nimalan Arinaminpathy
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Article
| Open AccessBedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis
Bedaquiline (BDQ) is a known tuberculosis treatment, but the precise mechanism of cell death is unclear. Here, the authors explore the metabolic profiles of M. tuberculosis upon BDQ treatment and find reliance on glycolysis and synergistic cell death when oxidative phosphorylation is also targeted.
- Jared S. Mackenzie
- , Dirk A. Lamprecht
- & Adrie J. C. Steyn
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Article
| Open AccessMetformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits
Metformin is an anti-diabetic drug that has shown promise to reduce M. tuberculosis susceptibility. Here the authors show that this effect is a result of metformin-mediated activation of anti-mycobacterial memory-like antigen-inexperienced CD8+CXCR3+ T cells, an effect that also boosts response to BCG vaccination.
- Julia Böhme
- , Nuria Martinez
- & Amit Singhal
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Article
| Open AccessRETRACTED ARTICLE: Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection
Kupffer cells are more resistant to M. tuberculosis when compared with alveolar macrophages. Here the authors show that this distinction is caused by the presence of ornithine and imidazole in Kupffer cells and that these metabolites can drive autophagy and M. tuberculosis killing in alveolar macrophages when given intranasally to infected mice.
- Ramya Sivangala Thandi
- , Rajesh Kumar Radhakrishnan
- & Ramakrishna Vankayalapati
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Article
| Open AccessCryo-EM structure of arabinosyltransferase EmbB from Mycobacterium smegmatis
The cryo-EM structure of Mycobacterium smegmatis arabinosyltransferase B EmbB involved in mycobacterial cell wall biosynthesis provides insights into the substrate binding and reaction mechanism. Mapping of the ethambutol resistance associated mutations onto the structure suggests the location of the drug binding site.
- Yong Zi Tan
- , José Rodrigues
- & Filippo Mancia
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Article
| Open AccessA biochemically-interpretable machine learning classifier for microbial GWAS
Current machine learning classifiers have been applied to whole-genome sequencing data to identify determinants of antimicrobial resistance, but they lack interpretability. Here the authors present a metabolic machine learning classifier that uses flux balance analysis to estimate the biochemical effects of alleles.
- Erol S. Kavvas
- , Laurence Yang
- & Bernhard O. Palsson
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Article
| Open AccessPlasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection
Inflammasome activation is a response to bacterial infection but can cause damage and spread infection. Here, the authors use live single-cell imaging to show two mechanisms by which M. tuberculosis causes damage to human macrophage cell plasma membranes, resulting in activation of the NLRP3 inflammasome, pyroptosis and release of infectious particles.
- Kai S. Beckwith
- , Marianne S. Beckwith
- & Trude H. Flo
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Article
| Open AccessMycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production
Some strains of Mycobacterium tuberculosis seem to be able to avoid host defense systems. Here the authors stratify patients by severity of tuberculosis and find correlations with the level of IL-1β production by macrophages exposed to these isolates.
- Jeremy Sousa
- , Baltazar Cá
- & Margarida Saraiva
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Article
| Open AccessPyrazinamide triggers degradation of its target aspartate decarboxylase
It has been shown that the bioactive component of pyrazinamide, pyrazinoic acid (POA), blocks coenzyme A biosynthesis in M. tuberculosis by binding to the aspartate decarboxylase PanD. Here the authors show that pyrazinamide triggers degradation of PanD by stimulating its degradation by the caseinolytic protease Clp.
- Pooja Gopal
- , Jickky Palmae Sarathy
- & Thomas Dick
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Article
| Open AccessHydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis
The importance of host-produced hydrogen sulfide (H2S) in microbial pathogenesis is poorly understood. Here, Saini et al. show that H2S alters Mycobacterium tuberculosis (Mtb) central metabolism, stimulates respiration to promote growth and TB disease, and upregulates the Dos regulon.
- Vikram Saini
- , Krishna C. Chinta
- & Adrie J. C. Steyn