Marinum Infection Research Articles

Effect of LPS, dsRNA or interferons on the phagocytosis of dying cells or mycobacteria by macrophages

Infection with intracellular pathogens can trigger a panel of innate immune responses including cell death. Coupled with phagocytosis this often leads to clearance of the invader. However, some pathogens use the process to disseminate and proliferate. During Mycobacterium marinum infection, dying infected macrophages recruit fresh ones to the site of granuloma formation. The recruited macrophages phagocytose infected cell remnants, get infected and die, thus ensuring efficient spread and multiplication of the pathogen. Maturation of granuloma, the characteristic lesions of tuberculosis, requires tumor necrosis factor (TNF) and interferon (IFN)-gamma and represents a stalemate between host and pathogen sufficient to arrest infection without eliminating the bacteria. Indeed, our macrophage / mycobacterial infection model demonstrates that virulent H37RvMycobacterium tuberculosis is more efficient in macrophage infection and killing than the attenuated Mycobacterium bovis BCG vaccine. Today it is still unclear whether the signal promoting macrophage engagement in phagocytosis is originating from a pathogen or the infected host, and whether the effect is general or target specific. Therefore, we used a quantitative cell line based assay to study the effects of PAMPs or cellular alarm signals on the phagocytic engagement and capacity of macrophages to engulf virulent or attenuated mycobacteria and dying cells. Our results demonstrate that pretreatment of macrophage like cells with double stranded RNA, lipopolysaccharide, type I or II IFN but not with TNF, can significantly increase their capacity to phagocytose apoptotic and necrotic cells but has little effect on the phagocytosis of free mycobacteria. Although this macrophage activation process is probably an innate immune response reinforcing the capacity of the host to dispose of dying infected cells, pathogens may exploit it for their propagation.

Nontuberculous Mycobacterial Tenosynovitis in the Hand: Two Case Reports with the MR Imaging Findings

Nontuberculous mycobacterial infections can cause destructive tenosynovitis of the hand. We report on and discuss the clinical course and distinctive radiologic findings of two patients with hand tenosynovitis secondary to M. marinum and intracellulare infection, which are different from those of the nontuberculous mycobacterial infections reported in the previous literature.

Aspects histopathologiques de l’infection à Mycobacterium marinum

Skin infection by Mycobacterium marinum induces the classic granuloma of aquariums and swimming pools. The histopathological signs have been described primarily in small series of typical cases, generally with no bacteriological evidence. In a national survey of proven infection with M. marinum detailed data was collected for 63 patients. The aim of this new study was to describe microscopic signs of the infection based upon biopsies taken from these patients. Unstained slides from 32 biopsies of the skin (n=24) or synovial biopsies (n=8) were prepared; they originated from 27 patients. They were examined after standard staining and after Ziehl-Neelsen staining, without knowledge of the clinical data. All biopsies were taken from the upper limb of 18 men and nine women of mean age 48 years. Tubercular granulomas were observed in only 60% of cases. The largest and most numerous were seen in the synovial samples. Due to their palisade appearance, they were occasionally impossible to distinguish from rheumatoid nodules. In 20% of cases, neutrophil collections were seen without granulomas and in remaining 20% of cases, relatively non-specific infiltrate was observed. Epidermal changes consisted in psoriasiform or pseudocarcinomatous hyperplasia, particularly at the edges of ulcerated areas; invasion of the dermo-epidermal junction was seen in five cases. Follicular necrosis was observed in four cases with lymphoplasmacytic infiltrates remote from the granulomas being seen in 22 biopsies. Ziehl-Neelsen staining revealed no bacilli. The originality of this series consists of bacteriological proof of M. marinum infection and the absence of biopsy selection based on clinical criteria. It shows that the typical granulomas are in fact present in less than two third of cases, and that these may be confused with rheumatoid nodules. The chief characteristic of these lesions is the very low concentration of microorganisms present, in contrast with other forms of mycobacterium, making them difficult to see; routine confirmation cannot thus be expected from specific staining procedures. In one case out of five, the infiltrate suggested no infectious origin, although deep skin biopsies and synovial biopsies provided more information. For all forms of necrotic granuloma, whether or not accompanied by collections of neutrophils, a culture should be carried out in a specific medium, even in the absence of microscopic evidence of bacilli.

Association analysis of the LTA4H gene polymorphisms and pulmonary tuberculosis in 9115 subjects

SummaryImmunoregulatory eicosanoids have been implicated in protection from mycobacterial infection in cell and animal models. Recently, a study of the zebrafish embryo demonstrated that mutants of the lta4h gene, which encodes the leukotriene A4 hydrolase (LTA4H) enzyme of the eicosanoid pathway, have hypersusceptibility to Mycobacterium marinum infection. It also reported that heterozygosity at the two single nucleotide polymorphisms rs1978331 and rs2660898 located in introns of the LTA4H gene, a human homologue of lta4h, is associated with protection from pulmonary tuberculosis. To replicate this association we genotyped six LTA4H gene polymorphisms in samples from 3703 pulmonary tuberculosis patients and 5412 healthy controls collected in Russia. We found no evidence of the protective effect of heterozygosity at the polymorphisms rs1978331 and rs2660898 (P = 0.29 and 0.49) and no association of the alleles of any of the six polymorphisms (P = 0.13–0.81). These results suggest that common polymorphisms in the LTA4H gene do not play any major role in susceptibility to clinical pulmonary tuberculosis.

Mycobacterium marinum infection in the setting of antitumor necrosis factor alpha therapy for Crohnʼs disease

Mycobacterium marinum infection in the setting of antitumor necrosis factor alpha therapy for Crohnʼs disease

Nodular lymphangitis: Report of a case with presentation of a diagnostic paradigm

A 54-year-old man with asthma, mitral valve prolapse, and a back injury developed erythematous nodules that progressed along the lymphatic drainage of his right arm. Skin biopsy revealed granulomatous inflammation with microabscess formation. Culture confirmed Mycobacterium marinum infection. The patient was treated with clarithromycin, ethambutol, rifampin, and topical silver sulfadiazine. Oral doxycycline hyclate was later added because of slow healing. Mycobacterium marinum is one of a group of infectious agents that can cause nodular lymphangitis. Sporotrichoid lesions most commonly develop after cutaneous inoculation with Sporothrix schenckii, Leishmania species, Nocardia species, and Mycobacterium marinum. A thorough clinical history and physical examination can narrow the differential diagnosis by eliciting information about the etiologic setting, incubation time, clinical appearance of the lesions, and presence or absence of systemic involvement for each of the causative organisms. Skin biopsy and microbiological tissue cultures are essential for diagnostic confirmation. The differential diagnosis and a suggested diagnostic paradigm will be reviewed.

Deep sequencing of the innate immune transcriptomic response of zebrafish embryos to Salmonella infection

Salmonella enterica serovar Typhimurium ( S. typhimurium) bacteria cause an inflammatory and lethal infection in zebrafish embryos. To characterize the embryonic innate host response at the transcriptome level, we have extended and validated previous microarray data by Illumina next-generation sequencing analysis. We obtained 10 million sequence reads from control and Salmonella-infected zebrafish embryos using a tag-based sequencing method (DGE or Tag-Seq) and 15 million reads using whole transcript sequencing (RNA-Seq), which respectively mapped to circa 65% and 85% of 28,716 known Ensembl transcripts. Both sequencing methods showed a strong correlation of sequence read counts per transcript and an overlap of 241 transcripts differentially expressed in response to infection. A lower overlap of 165 transcripts was observed with previous microarray data. Based on the combined sequencing-based and microarray-based transcriptome data we compiled an annotated reference set of infection-responsive genes in zebrafish embryos, encoding transcription factors, signal transduction proteins, cytokines and chemokines, complement factors, proteins involved in apoptosis and proteolysis, proteins with anti-microbial activities, as well as many known or novel proteins not previously linked to the immune response. Furthermore, by comparison of the deep sequencing data of S. typhimurium infection in zebrafish embryos with previous deep sequencing data of Mycobacterium marinum infection in adult zebrafish we derived a common set of infection-responsive genes. This gene set consists of known and putative innate host defense genes that are expressed both in the absence and presence of a fully developed adaptive immune system and that provide a valuable reference for future studies of host–pathogen interactions using zebrafish infection models.

Dissémination lymphangitique et greffe sur implant contraceptif de Mycobacterium marinum

We report a 37-year-old woman who presented a cutaneous papulonodular skin eruption with sporotrichoid topographic distribution. The diagnosis of Mycobacterium marinum infection was obtained with the bacteriological examination of a cutaneous biopsy and related to cleaning her aquarium at home. Mycobacteriological grown on a subdermal contraceptive implant had not been published before.

Mycobacterium marinum infection following kayaking injury

Mycobacterium marinum infection following kayaking injury

Possible role of anti-TNF monoclonal antibodies in the treatment of Mycobacterium marinum infection

Possible role of anti-TNF monoclonal antibodies in the treatment of Mycobacterium marinum infection

Host-Detrimental Role of Esx-1-Mediated Inflammasome Activation in Mycobacterial Infection

The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1β, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome.

Review Article: Mycobacterium Marinum Infection of the Hand and Wrist

Misdiagnosis and delayed treatment of Mycobacterium marinum infection is common because of its diverse manifestations. This leads to inappropriate use of antimicrobials, extension of the infection from the skin to the tenosynovium, and a poor prognosis (loss of tendons and prolonged immobilisation, secondary to multiple debridements and joint contractures). Clinicians should be aware of this type of infection, especially in subjects at risk (fishermen and aquarium enthusiasts), and those with a history of trauma coupled with exposure to water or marine life. A proactive approach to obtain a biopsy for histopathological and microbiological diagnosis is advised. Anti-mycobacterial treatment should be started promptly. The combined use of rifampicin, ethambutol, and clarithromycin appears to be effective, and debridement is indicated in patients with deep-seated infections.

Chronic Ulceration from Mycobacterium marinum Infection and the Diagnostic Value of T-Cell Interferon-γ Release Assays

This case report describes the differential diagnosis of cutaneous ulcerations and the utility of the interferon-gamma release assays as a tool to aid in the diagnosis. These new assays can be used to identify mycobacterial infections (specifically Mycobacterium marinum) as the etiologic agents.

Mycobacterium marinum infection complicated by anti-tumour necrosis factor therapy

Mycobacteria other than tuberculosis infections in patients taking various tumour necrosis factor (TNF)-alpha inhibitors have been reported in the literature. We describe sporotrichoid spread of Mycobacterium marinum in a man with Crohn's disease treated with infliximab. After starting ethambutol and rifampicin and discontinuing infliximab, a worsening appeared. M. marinum infection may have a potential local spread and systemic dissemination in patients treated with TNF-alpha inhibitors.

Sporotrichoid Mycobacterium marinum infection of the face following a cat scratch

Mycobacterium marinum infections in humans uncommonly affect the face and are not known to be associated with cat scratches. We describe a 24-year-old woman who presented with a 3-month history of multiple tender, occasionally discharging cystic nodules involving the left side of her face in a sporotrichoid distribution. She had suffered a cat scratch to her left lower eyelid 3 weeks before the onset of the eruption and owned multiple tropical fish tanks. She was systemically well and had no lymphadenopathy. She had a background history of a 4.5-mm-thick nodular melanoma of her temple treated by wide local excision and negative sentinel lymph node biopsy 4 years prior. Skin biopsies showed multiple variably sized granulomas surrounded by thick cuffs of lymphocytes involving the superficial and deep dermis with no organisms seen on Ziehl-Neelsen, peroidic acid-Schiff and methenamine silver stains. Laboratory investigations showed a mildly raised erythrocyte sedimentation rate but normal full blood count and C-reactive protein. Fluid from the left cheek grew an acid-fast bacillus identified as Mycobacterium marinum. The skin eruption cleared after 5-month treatment with oral clarithromycin 500 mg twice daily and rifampicin 600 mg daily.

Extranodal Natural Killer Cell/T-Cell Lymphoma, Nasal Type, Presenting as Cutaneous Nodules and a Small-Bowel Perforation

Extranodal natural killer (NK) cell/T-cell lymphoma, nasal type, is a rare aggressive neoplasm, most commonly presenting as a destructive lesion in the nasal cavity and nasopharynx in middle-aged to older adults. About one third of cases present in an extranasal location, commonly involving skin and gastrointestinal tract, and usually occur in the absence of superficial lymphadenopathy. Diagnosis of this malignancy can be missed given its rarity and heterogeneous presentation. We describe a patient with an extranodal NK cell/T-cell lymphoma, nasal type, who was initially diagnosed and treated for a presumed Mycobacterium marinum infection, after biopsies were unrevealing. However, after more serious complications developed, repeat biopsy was performed. An atypical lymphocytic infiltrate was noted, with cells being positive for NK cell/T-cell markers CD2, CD7, and CD3 (subset), as well as for cytotoxic lymphocyte markers perforin, T-cell intracellular antigen, and CD56. In situ hybridization for Epstein-Barr virus-encoded RNA was also positive. This case demonstrates an important diagnostic pitfall of confusing cutaneous involvement by an aggressive NK cell/T-cell lymphoma with an antibiotic-resistant infection. Repeat biopsies and close clinicopathologic correlation are essential for establishment of correct diagnosis.

MYCOBACTERIUM MARINUMINFECTION OF THE DEEP STRUCTURES OF THE HAND AND WRIST: 25 YEARS OF EXPERIENCE

Mycobacterium marinum infection could have various presentations, from superficial skin infection to deep structure destruction. The prognosis is relatively poor when deep structure is involved as it is more destructive. The prognosis is even worse when operation is required. In the retrospective study of 136 patients who suffered this disease with deep structure involvement, their clinical presentations could be classified into benign and aggressive type. It was found that both types of presentation could be treated conservatively by medication alone. Benign presentations could be treated successfully with chemotherapy alone without complications. Patients with aggressive presentation were usually associated with worse prognosis as there were more complications regardless of the management option. Therefore, the clinical presentation not only had prognostic value but could also guide the treatment plan.

Nontuberculous Mycobacteria in Solid Organ Transplant Recipients

Nontuberculous Mycobacteria in Solid Organ Transplant Recipients

Infection cutanée aiguë et nécrosante à Mycobacterium marinum chez un patient traité par infliximab pour une maladie de Crohn

The increasing use of anti-TNFalpha exposes patients to emerging risks, particularly that of infection. We report a case of severe cutaneous Mycobacterium marinum infection in a patient treated with infliximab and we discuss therapeutic options. A man treated with infliximab for Crohn's disease developed a severe cutaneous infection with M. marinum. Despite withdrawal of infliximab and the introduction of triple antibiotic therapy, the patient's lesions worsened and surgical treatment was required. The worsening experienced by our patient 1 week after the beginning of the treatment is comparable with the immune reconstitution syndrome occasionally observed in tuberculosis in immunocompromised hosts, thus raising the question of the potential value of continuing infliximab treatment. Recommendations are needed concerning the prevention and treatment of M. marinum infections in patients on anti-TNFalpha biotherapies.

Disseminated Mycobacterium marinum infection in a patient with rheumatoid arthritis receiving infliximab therapy

Tumor necrosis factor-alpha inhibitors are important adjunctive therapies for rheumatologic diseases. These agents increase the risk for granulomatous disease. We present a case of a woman with severe rheumatoid arthritis on infliximab who developed multiple nodular skin lesions. Biopsies grew Mycobacterium marinum. New lesions developed through therapy, necessitating surgical debulking.