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A conserved grain-associated immunosuppressive niche in Sudanese patients with mycetoma.

Mycetoma is a neglected tropical disease caused by various bacterial and fungal pathogens that has a significant health impact across a broad geographically defined "mycetoma belt" spanning South America, Africa and Asia. Histologically, mycetoma is characterised by invasive and destructive granuloma development in the skin, deep tissues and bone, leading to tissue destruction, deformities and high morbidity. The presence of macroscopic, highly compacted pathogen microcolonies, or "grains," is a key diagnostic feature, and the formation of grains supports pathogen persistence and disease chronicity. However, there is a paucity of information on immune responses in mycetoma patients and on the relative importance of phylogeny and/or grains in establishing the local immune landscape. Here, we used spatial proteomics to examine the distribution of 43 immune-related proteins in surgical biopsies from 11 patients with mycetoma of bacterial (actinomycetoma; Actinomadura pelletierii and Streptomyces somaliensis; n = 6) and fungal (eumycetoma; Madurella mycetomatis; n = 5) origin. Using mixed-effects modelling, an exploratory analysis across species and pathogen classes revealed few significant differences in immune marker expression. In contrast, and independently of pathogen class, the cellular infiltrate closest to grain boundaries had higher per-cell expression of CD66b+ neutrophils, ARG1, and VISTA. The preferential accumulation of CD66b+ARG1+VISTA+ cells at grain boundaries was confirmed by quantitative immunofluorescence analysis. Hence, the local tissue microenvironment surrounding the mycetoma grain represents a specialised immunosuppressive niche, with parallels to the tumour microenvironment. Trial Registration The study was prospectively registered on ClinicalTrials.gov NCT04401969.

Adult

Mycetomas in pulmonary sarcoidosis: non-surgical management.

The course and prognosis of all patients with mycetomas in the setting of pulmonary sarcoidosis from 1960 to 1978 were reviewed. Twelve patients were identified. All patients were managed conservatively without surgery or antifungal agents. Three patients died; however, only one death could be attributed to the presence of a mycetoma and all deaths were associated with severe pulmonary insufficiency. Episodes of both major and minor hemoptysis were managed successfully with supportive therapy alone in the remaining nine patients. Survival after the diagnosis of a mycetoma was 10-14 years in three patients, 5-7 years in three patients and 3-4 years in three patients. All nine surviving patients have required corticosteroids for control of their underlying sarcoidosis. Extracavitary invasive disease due to Aspergillus organisms was not seen in this group. In the setting of chronic pulmonary sarcoidosis with mycetoma formation, fatal hemoptysis is infrequent and episodes of hemorrhage may be safely managed with supportive medical therapy alone.

Adolescent

Mycetomas in Madras.

In 90 of 150 cases clinically diagnosed as mycetoma in the Department of Pathology, Madras Medical College, from January 1964 to June 1975, histopathological study revealed granules. Besides special staining procedures, cultural methods were undertaken in recent cases. The age and sex incidence, site of lesion and the species of fungi identified on the basis of histological morphology of the granules are analysed. The disease was predominatly seen in the age group 21-40. Men were more frequently affected than women and the commonest site of the lesion was foot. Actinomycotic mycetoma (68-9%) was more often found than the maduromycotic type. Madurella mycetomi (37-8%) and Actinomadura madurae (26-7%) were the commonest causal agents. Nocardia spp. were the next most common (21-1%) followed by A. pelletieri (15-5%), S. somaliensis (5-6%) and presumably Allescheria/Cephalosporium spp. from only 3 cases of white grain mycetoma.

Acremonium

Mycetomas in goats.

Naturally occurring mycetomas were found in 3 goats. Two had mycetomas on their hind legs and the third on its left scapula. In 2 goats the causative agents were identified by culture, histopathology and serology as Actinomadura madurae. In the remaining goat diagnosis was based only on histopathology and the causative agent was considered to be A. pelletierii. Despite minor differences between goat and human strains of A. madurae, it would seem that goats could be useful experimental models.

Actinomycetales

Comparative virulence and immunodiffusion analysis of Petriellidium boydii (Shear) Malloch strains isolated from feedlot manure and a human mycetoma.

The virulence to mice of a Petriellidium boydii strain isolated from feedlot manure was compared with that of a strain from a human mycetoma. Washed spores suspended in 5% hog gastric mucin were injected intraperitoneally into non-inbred female albino Swiss mice. In 21 days, the mycetoma strain killed 95% of the test animals whereas injection of eight times as many feedlot strain spores resulted in only 28% mortality. A progressive, exclusively sinistral (leftsided) torticollis was the most obvious symptom of experimental petriellidiosis. Mycelia bearing annellospores were observed in PAS-stained sections of most internal organs, including the brains, of the test animals. Immunodiffusion analyses were conducted on soluble antigen preparations with concentrated antisera produced in rabbits using live spore suspensions. The two strains contained common antigen but the proportions of two were significantly different.

Animals

The migrating mycetoma.

A case of mycetoma is presented in which the fungus ball migrated from the apex to the base of the lung as a result of progressive parencyhmal destruction by tuberculosis. Histological and serological data suggested Aspergillus fumigatus as the cause of the mycetoma. Aspergillomas rarely coexist in cavities with active tuberculosis.

Aspergillus fumigatus

[Histo-pathological features of African mycetomas (author's transl)].

From a review of 94 original cases of mycetoma, a description of the most important histo-pathological features of these tumors is given. The microscopic diagnosis of mycetoma is easy and so is generally the identification of the responsible agent, either a bacteria or a fungus. In every case and specially in atypic ones a mycological study is necessary to ascertain the aetiological diagnosis.

Africa

Botryomycosis. A bacterial cause of mycetoma.

Botryomycosis is a chronic, granulomatous, bacterial infection in which grains are produced. Clinically, it may not be distinguished from a mycetoma of fungal origin. A case is reported in which the causative organisms were Staphylococcus aureus and Pseudomonas aeruginosa.

Child

Black grain mycetoma: the ultrastructure of Madurella mycetomi.

Madurella mycetomi, the fungus pathogen of black grain mycetoma, shows an elaborate development of mesosomes as its most striking ultrastructural feature. These occur in addition to mitochondria and endoplasmic reticulum. Condensations of hyphal cytoplasm and recurring intrahyphal growth of new hyphal cells are features of the pigment-producing and pathogenic phases of the organism. The abundant pigment which histochemically resembled melanin was not traceable to any ultrastructural granule, nor was it built from a tyrosine precursor. The ultrastructural changes occurring in collagen through a sclerotizing action by the fungus are briefly noted.

Catechols

Preliminary investigation of the use of the enzyme linked immunosorbent assay (ELISA) in the serodiagnosis of mycetoma.

Antibody levels in a small group of Sudanese patients with clinically diagnosed mycetoma, and control groups were measured by countercurrent immunoelectrophoresis (CIE) and enzyme linked immunosorbent assay (ELISA). Antigens were prepared from the following organisms: Streptomyces somaliensis, Actinomadura madurae, A. pelletieri, Nocardia brasiliensis and Madurella mycetomi. Positive reactions were obtained in clinical cases against the homologous antigens in both CIE and ELISA; all heterologous and control sera negative in CIE but produced some reaction particularly against N. brasiliensis and M. mycetomi antigens in ELISA.

Antigens, Bacterial

Mycetomas in North India.

Of 60 clinically suspected cases of mycetoma, 20 were confirmed by cultural and histopathological methods. The feet were found to be affected in 70% of the cases. The age group most affected by the disease was 20-40 years. Men were involved in 18 while females were affected in 2 cases only. Actinomycetomas (70%) were found more often than eumycetomas (30%). Nocardia species were identified in 35% of cases and Madurella mycetomi in 25%. There were four cases (20%) where the etiological agents could not be identified; these were suspected to be due to Actinomadura madurae. A. pelletieri, A. madurae, an unidentified anaerobic actinomyces, and Phialophora jeanselmei, were identified in one case each.

Actinomycetales

Eumycotic mycetoma due to Drechslera rostrata infection in a cow.

A case of eumycotic mycetoma with lesions in the skin, nasal cavity and lymph nodes of a cow is reported. The case history, clinical course, macroscopic and microscopic appearance of lesions, and fungal isolation are described. Drechslera rostrata was isolated from pathological tissue and Koch's postulates were satisfied on mouse inoculation. This is the first infection of its type recorded in Australia and features contrasting with cases reported in other countries are discussed.

Animals

[Mycetoma in Somalia - results of a survey done from 1959 to 1964].

The Pasteur Institute studied 103 mycetoma patients in Somalia between 1959 and 1964. Grains were seen in 94 of them and this, added to cultural features, allowed the diagnosis of 60 pathogens as follows: 44 Madurella mycetomi, 1 Leptosphaeria senegalensis, 7 Pyrenochaeta romeroi (or Madurella grisea), 3 Allescheria boydii, 1 Fusarium sp., 3 Neotestudina (Zopfia) rosatii, and 1 unidentified; 34 were actinomycetes: 24 Streptomyces somaliensis, 4 Actinomadura madurae, 3 A. pelletieri and 3 Nocardia spp. The patients delayed too long in consulting their doctors and health education is vital if amputations are to be avoided. The geographical distribution is related to climate and fungal species. In central Somalia the association of M. mycetomi and S. somaliensis, organisms characteristic of desert conditions, was found; white grain mycetomata and those caused by Nocardia spp. occurred in more humid areas. The study revealed 2 new fungi. One, obtained in culture was called Neotestudina (Zopfia) rosatii. The 3 patients affected, lived in Mudugh (2 in El Bur). The other fungus was not identified. It also was recovered from El Bur and one with similar microscopic characters has been seen in Chad and also in "territoire français des Afars et des Issas". Both fungi are desert species.

Acremonium

[Value of radiology for the diagnosis of mycetomas (author's transl)].

Mycetomas have raised a new interest because of cases introduced from tropical areas to non endemic countries, and because of the emergence in these countries of autochthonous cases in immuno-depressed patients. Radiologic diagnosis is no more limited to the description of osseous changes, the basic aspects of which are characteristic: cortical erosion, periosteous condensation and reaction. Using modern radiological technics such as arteriography and lymphography, gives a possibility to appreciate more thoroughly the extension and the potential evolution, so that the radiological approach may be similar to that of carcinology.

Africa

[Agents of mycetomas: a bacteriological and parasitological study (author's transl)].

Microscopic agents responsible of Mycetomas are reviewed. They may be bacteria belonging to the Actinomycetalae order (Nocardia, Actinomadura, Streptomyces) or very various fungi belonging to the classes of Adelomycetes or Ascomycetes (Madurella, Leptosphaeria, Neotestudina, etc.). Though the procedures for collecting and transporting samples are the same, direct microscopic examination gives possibility to choose among the selective culture media the most appropriate ones to isolate either fungi or Actinomycetalae. Technics of identification for the most important bacterial agents are given, but fungi can be identified in only very specialized laboratories. Immunological methods may bring valuable indications for helping diagnosis or treatment supervision.

Actinomycetales

Acremonium recifei as an agent of mycetoma in India.

Acremonium recifei was identified as the causal agent in a case of white grain eumycotic mycetoma of the hand which occurred in South India. The identification was based on the structure of the granules in tissue and on the morphological characteristics of the culture obtained from the granules. This case represents the first documented instance in which A. recifei has been found outside of Latin America.

Adult

Unusual manifestations of mycetoma.

Five cases of mycetoma of bone involving patella, shaft of tibia, medial malleolus, calcaneum and phalanx of great toe are presented. In all the cases bones were extensively damaged with minimal or no involvement of soft tissue, a very unusual feature. Aetiopathogenesis involvement of bone substantiated by facts, is discussed.

Adult