-
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 -
Microbiology Spectrum Apr 2017Mycobacterium marinum is a well-known pathogenic mycobacterium for skin and soft tissue infections and is associated with fishes and water. Among nontuberculous... (Review)
Review
Mycobacterium marinum is a well-known pathogenic mycobacterium for skin and soft tissue infections and is associated with fishes and water. Among nontuberculous mycobacteria (NTM), it is the leading cause of extrarespiratory human infections worldwide. In addition, there is a specific scientific interest in M. marinum because of its genetic relatedness to Mycobacterium tuberculosis and because experimental infection of M. marinum in fishes mimics tuberculosis pathogenesis. Microbiological characteristics include the fact that it grows in 7 to 14 days with photochromogenic colonies and is difficult to differentiate from Mycobacterium ulcerans and other mycolactone-producing NTM on a molecular basis. The diagnosis is highly suspected by the mode of infection, which is related to the hobby of fishkeeping, professional handling of marine shells, or swimming in nonchlorinated pools. Clinics distinguished skin and soft tissue lesions (typically sporotrichoid or subacute hand nodules) and lesions disseminated to joint and bone, often related with the local use of corticosteroids. In clinical microbiology, microscopy and culture are often negative because growth requires low temperature (30°C) and several weeks to succeed in primary cultivation. The treatment is not standardized, and no randomized control trials have been done. Therapy is a combination of surgery and antimicrobial agents such as cyclines and rifampin, with successful outcome in most of the skin diseases but less frequently in deep tissue infections. Prevention can be useful with hand protection recommendations for professionals and all persons manipulating fishes or fish tank water and use of alcohol disinfection after contact.
Topics: Animals; Disease Susceptibility; Ecosystem; Fish Diseases; Fishes; Humans; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Skin Diseases, Bacterial; Water Microbiology
PubMed: 28387180
DOI: 10.1128/microbiolspec.TNMI7-0038-2016 -
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 -
The Veterinary Quarterly Dec 2018Mycobacterium marinum is an opportunistic pathogen inducing infection in fresh and marine water fish. This pathogen causes necrotizing granuloma like tuberculosis,... (Review)
Review
Mycobacterium marinum is an opportunistic pathogen inducing infection in fresh and marine water fish. This pathogen causes necrotizing granuloma like tuberculosis, morbidity and mortality in fish. The cell wall-associated lipid phthiocerol dimycocerosates, phenolic glycolipids and ESAT-6 secretion system 1 (ESX-1) are the conserved virulence determinant of the organism. Human infections with Mycobacterium marinum hypothetically are classified into four clinical categories (type I-type IV) and have been associated with the exposure of damaged skin to polluted water from fish pools or contacting objects contaminated with infected fish. Fish mycobacteriosis is clinically manifested and characterized in man by purple painless nodules, liable to develop into superficial crusting ulceration with scar formation. Early laboratory diagnosis of M. marinum including histopathology, culture and PCR is essential and critical as the clinical response to antibiotics requires months to be attained. The pathogenicity and virulence determinants of M. marinum need to be thoroughly and comprehensively investigated and understood. In spite of accumulating information on this pathogen, the different relevant data should be compared, connected and globally compiled. This article is reviewing the epidemiology, virulence factors, diagnosis and disease management in fish while casting light on the potential associated public health hazards.
Topics: Animals; Fish Diseases; Fishes; Humans; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Water Microbiology; Zoonoses
PubMed: 29493404
DOI: 10.1080/01652176.2018.1447171 -
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 -
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 -
Infection Dec 2015Invasive Mycobacterium marinum disease (tenosynovitis and osteomyelitis) may be an increasingly common manifestation of M. marinum infection that presents unique... (Review)
Review
PURPOSE
Invasive Mycobacterium marinum disease (tenosynovitis and osteomyelitis) may be an increasingly common manifestation of M. marinum infection that presents unique diagnostic and therapeutic challenges. We conducted a retrospective case series and literature review of M. marinum infection to better understand the clinical spectrum of invasive versus cutaneous disease.
METHODS
We reviewed electronic medical records for all M. marinum infections at Duke University Medical Center from January 1, 1996 to April 30, 2014. Published case series of M. marinum infection since 1990 reporting >5 cases were systematically ascertained and reviewed.
RESULTS
Twenty-eight cases of M. marinum infection were identified from our institution. Twenty cases (87 %) involved aquatic exposure, and 26 (93 %) involved finger and/or hand lesions. Median time to diagnosis was 3.5 months. Nineteen (68 %) cases had invasive infection, and 9 (32 %) were cutaneous; invasive infection was more common with older age. Granulomatous inflammation and acid-fast bacilli were noted on pathologic examination in 11 (58 %) and 3 (16 %) cases, respectively. Primarily monotherapy was used in 2 (12 %) cases, dual therapy in 8 (47 %) cases, and three-drug therapy in 7 (41 %) cases; three-drug therapy was more common with invasive infection. Median duration of treatment was 5 months. Adjunctive surgery was performed for 18 (95 %) cases of invasive infection and 4 (44 %) of cutaneous infection. Twenty-one (75 %) cases improved, while 7 (25 %) were lost to follow-up.
CONCLUSIONS
Distinguishing between invasive and cutaneous M. marinum infection may have important consequences in terms of antibiotic choice and need for adjunctive surgery.
Topics: Adult; Aged; Anti-Bacterial Agents; Female; Hospitals, University; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; North Carolina; Osteomyelitis; Retrospective Studies; Skin Diseases, Bacterial; Tenosynovitis; Treatment Outcome
PubMed: 25869820
DOI: 10.1007/s15010-015-0776-8