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.