-
Cell Sep 2022Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a...
Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
Topics: Animals; Mycobacterium marinum; Mycobacterium tuberculosis; TOR Serine-Threonine Kinases; Tuberculosis; Zebrafish
PubMed: 36103894
DOI: 10.1016/j.cell.2022.08.018 -
Cell Nov 2022The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak...
The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.
Topics: Animals; Humans; Zebrafish; Mycobacterium tuberculosis; Tuberculosis; Macrophages; Bone Diseases; Bacterial Proteins; Mycobacterium marinum
PubMed: 36356582
DOI: 10.1016/j.cell.2022.10.019 -
Cell Sep 2019Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular...
Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.
Topics: Animals; Apoptosis; Calcium; Endoplasmic Reticulum; Humans; Lysosomes; Macrophages; Membrane Potential, Mitochondrial; Mitochondria; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Mycobacterium tuberculosis; Necrosis; Reactive Oxygen Species; THP-1 Cells; Tuberculosis; Tumor Necrosis Factor-alpha; Zebrafish
PubMed: 31474371
DOI: 10.1016/j.cell.2019.08.004 -
Journal of Clinical Microbiology Mar 2020
PubMed: 32213576
DOI: 10.1128/JCM.02059-18 -
Microorganisms Jul 2023Skin and soft tissue infections caused by non-tuberculous mycobacteria are occurring more frequently in recent years. However, chronic skin and soft tissue lesions... (Review)
Review
Skin and soft tissue infections caused by non-tuberculous mycobacteria are occurring more frequently in recent years. However, chronic skin and soft tissue lesions present a challenge for clinicians, as the diagnostic work-up and definitive diagnosis require knowledge and available laboratory resources. We present here the case of a 66-year-old male patient who presented with painful abscess-like nodules on his right hand and forearm, which worsened after treatment with an anti-TNF-a agent. The fluid specimen taken from the lesion was positive for mycobacteria according to the acid-fast stain. was identified, first by next-generation sequencing and finally grown on culture, after eight weeks. Acknowledging the complexity of diagnosing and managing infections by non-tuberculous mycobacteria, and especially , we provide a review of the current epidemiology, clinical characteristics, diagnosis and management of infection.
PubMed: 37512971
DOI: 10.3390/microorganisms11071799 -
Microbiology and Molecular Biology... Nov 2020Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. causes both acute and chronic human... (Review)
Review
Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for virulence and is functionally conserved between and is an NTM found in both salt water and freshwater that is often used to study mycobacterial virulence. Since the discovery of the secretion system in 2003, the use of both and has defined the conserved molecular mechanisms underlying protein secretion and the lytic and regulatory activities of the ESX-1 system. Here, we review the trajectory of the field, including key discoveries regarding the ESX-1 system. We highlight the contributions of studies and the conserved and unique aspects of the ESX-1 secretion system.
Topics: Animals; Bacterial Proteins; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions; Humans; Models, Biological; Mycobacterium marinum; Mycobacterium tuberculosis; Protein Transport; Tuberculosis; Type VII Secretion Systems; Virulence
PubMed: 32878966
DOI: 10.1128/MMBR.00082-19 -
Open Forum Infectious Diseases Apr 2022is a nontuberculous mycobacterium that causes skin and soft tissue infections. Treatment consists of multiple antibiotics, sometimes combined with surgical debridement....
BACKGROUND
is a nontuberculous mycobacterium that causes skin and soft tissue infections. Treatment consists of multiple antibiotics, sometimes combined with surgical debridement. There is little evidence for the choice of antibiotics, the duration of treatment, and the role of susceptibility testing.
METHODS
We performed a retrospective cohort study of culture-confirmed infections in the Netherlands in the 2011-2018 period. Clinical characteristics, in vitro susceptibility, extent of disease, treatment regimens, and outcomes were analyzed. Incidence was assessed from laboratory databases.
RESULTS
Forty cases of infection could be studied. Antibiotic treatment cured 36/40 patients (90%) after a mean treatment duration of 25 weeks. Failure/relapse occurred in 3 patients, and 1 patient was lost to follow-up. Antibiotic treatment consisted of monotherapy in 35% and 2-drug therapy in 63%. Final treatment contained mostly ethambutol-macrolide combinations (35%). Eleven patients (28%) received additional surgery. We recorded high rates of in vitro resistance to tetracyclines (36% of isolates). Tetracycline resistance seemed correlated with poor response to tetracycline monotherapy. The annual incidence rate was 0.15/100000/year during the study period.
CONCLUSIONS
Prolonged and susceptibility-guided treatment results in a 90% cure rate in disease. Two-drug regimens of ethambutol and a macrolide are effective for moderately severe infections. Tetracycline monotherapy in limited disease should be used vigilantly, preferably with proven in vitro susceptibility.
PubMed: 35308482
DOI: 10.1093/ofid/ofac077 -
Cell Apr 2021The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma...
The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection.
Topics: Animals; Animals, Genetically Modified; Cadherins; Cell Differentiation; Disease Models, Animal; Epithelioid Cells; Granuloma; Hematopoietic Stem Cells; Immunity; Interferon-gamma; Interleukin-12; Macrophages; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Necrosis; Receptors, Interleukin-4; STAT6 Transcription Factor; Signal Transduction; Zebrafish; RNA, Guide, CRISPR-Cas Systems
PubMed: 33761328
DOI: 10.1016/j.cell.2021.02.046