Abstract 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. The study was prospectively registered on ClinicalTrials.gov ( NCT04401969 ). Author summary Mycetoma is a devastating disease found in tropical countries that causes high levels of tissue damage, often leading to amputation of affected limbs. Various bacterial and fungal pathogens cause the disease, but this does not affect how the disease appears. A common feature of mycetoma that helps doctors distinguish it from other diseases is the presence of “grains” in the tissues, which are discharged through the open sinuses. Under the microscope, they appear as colonies of the pathogen, together with host cell debris. It has been speculated that these grains allow the pathogen to resist immune attack and therefore contribute to the chronic nature of the infection. To understand how this may occur, we used spatial profiling and immunohistology to map the locations of multiple immune markers in the tissues of patients diagnosed with mycetoma. Our results show that phagocytic cells (neutrophils) in closest proximity to grains express molecules associated with immunosuppression. Similar neutrophils are found in close association with tumour cells in patients with cancer, where they inhibit host immunity and reduce the effectiveness of anti-tumour drugs. We speculate that these cells may play a similar role in mycetoma patients.
Osman et al. (2026) studied this question.