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Clinical Microbiology Reviews Jan 2018Humans encounter mycobacterial species due to their ubiquity in different environmental niches. In many individuals, pathogenic mycobacterial species may breach our... (Review)
Review
Humans encounter mycobacterial species due to their ubiquity in different environmental niches. In many individuals, pathogenic mycobacterial species may breach our first-line barrier defenses of the innate immune system and modulate the activation of phagocytes to cause disease of the respiratory tract or the skin and soft tissues, sometimes resulting in disseminated infection. Cutaneous mycobacterial infections may cause a wide range of clinical manifestations, which are divided into four main disease categories: (i) cutaneous manifestations of infection, (ii) Buruli ulcer caused by and other related slowly growing mycobacteria, (iii) leprosy caused by and , and (iv) cutaneous infections caused by rapidly growing mycobacteria. Clinically, cutaneous mycobacterial infections present with widely different clinical presentations, including cellulitis, nonhealing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis, verrucous lesions, and other types of findings. Mycobacterial infections of the skin and subcutaneous tissue are associated with important stigma, deformity, and disability. Geography-based environmental exposures influence the epidemiology of cutaneous mycobacterial infections. Cutaneous tuberculosis exhibits different clinical phenotypes acquired through different routes, including via extrinsic inoculation of the tuberculous bacilli and dissemination to the skin from other sites, or represents hypersensitivity reactions to infection. In many settings, leprosy remains an important cause of neurological impairment, deformity, limb loss, and stigma. , a mycobacterial species related to , is linked to diffuse lepromatous leprosy of Lucio and Latapí. produces a mycolactone toxin that leads to subcutaneous tissue destruction and immunosuppression, resulting in deep ulcerations that often produce substantial disfigurement and disability. , a close relative of , is an important cause of cutaneous sporotrichoid nodular lymphangitic lesions. Among patients with advanced immunosuppression, , the complex, and may cause cutaneous or disseminated disease. Rapidly growing mycobacteria, including the group, , and , are increasingly recognized pathogens in cutaneous infections associated particularly with plastic surgery and cosmetic procedures. Skin biopsies of cutaneous lesions to identify acid-fast staining bacilli and cultures represent the cornerstone of diagnosis. Additionally, histopathological evaluation of skin biopsy specimens may be useful in identifying leprosy, Buruli ulcer, and cutaneous tuberculosis. Molecular assays are useful in some cases. The treatment for cutaneous mycobacterial infections depends on the specific pathogen and therefore requires a careful consideration of antimicrobial choices based on official treatment guidelines.
Topics: Animals; Dermatitis; Humans; Mycobacterium; Mycobacterium Infections
PubMed: 30429139
DOI: 10.1128/CMR.00069-18 -
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 -
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 -
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 -
MBio Oct 2023Tuberculosis still remains a global burden and is one of the top infectious diseases from a single pathogen. , the causative agent, has perfected many ways to replicate...
Tuberculosis still remains a global burden and is one of the top infectious diseases from a single pathogen. , the causative agent, has perfected many ways to replicate and persist within its host. While mycobacteria induce vacuole damage to evade the toxic environment and eventually escape into the cytosol, the host recruits repair machineries to restore the MCV membrane. However, how lipids are delivered for membrane repair is poorly understood. Using advanced fluorescence imaging and volumetric correlative approaches, we demonstrate that this involves the recruitment of the endoplasmic reticulum (ER)-Golgi lipid transfer protein OSBP8 in the / system. Strikingly, depletion of OSBP8 affects lysosomal function accelerating mycobacterial growth. This indicates that an ER-dependent repair pathway constitutes a host defense mechanism against intracellular pathogens such as .
Topics: Humans; Vacuoles; Dictyostelium; Endoplasmic Reticulum; Mycobacterium marinum; Mycobacterium tuberculosis; Tuberculosis
PubMed: 37676004
DOI: 10.1128/mbio.00943-23