Eosinophils are remarkably recruited during schistosomiasis mansoni, one of the most common parasitic diseases worldwide. These cells actively migrate and accumulate at sites of granulomatous inflammation termed granulomas, the main pathological feature of this disease. Eosinophils colonize granulomas as a robust cell population and establish complex interactions with other immune cells and with the granuloma microenvironment. Eosinophils are the most abundant cells in granulomas induced by Schistosoma mansoni infection, but their functions during this disease remain unclear and even controversial. Here, we explore the current information on eosinophils as components of Schistosoma mansoni granulomas in both humans and natural and experimental models and their potential significance as central cells triggered by this infection.

Eosinophil sombrero vesicles are large tubular carriers resident in the cytoplasm of human eosinophils, identifiable by transmission electron microscopy, and important for immune mediator transport. Increased formation of sombrero vesicles occurs in activated eosinophils in vitro and in vivo. In tissue sites of eosinophilic cytolytic inflammation, extracellular eosinophil sombrero vesicles are noted, but their frequency and significance in eosinophil-associated diseases remain unclear. Here, we performed comprehensive quantitative transmission electron microscopy analyses and electron tomography to investigate the numbers, density, integrity, and 3-dimensional structure of eosinophil sombrero vesicles in different biopsy tissues from 5 prototypic eosinophil-associated diseases (eosinophilic chronic rhinosinusitis/nasal sinuses, ulcerative colitis/intestines, hypereosinophilic syndrome/skin, dermatitis/skin, and schistosomiasis/rectum). The morphology of extracellular eosinophil sombrero vesicles was also compared with that of cytoplasmic eosinophil sombrero vesicles, isolated by subcellular fractionation from peripheral blood eosinophils. We demonstrated that (i) eosinophil cytolysis, releasing intact sombrero vesicles and membrane-bound granules, is a consistent event in all eosinophil-associated diseases; (ii) eosinophil sombrero vesicles persist intact even after complete disintegration of all cell organelles, except granules (late cytolysis); (iii) the eosinophil sombrero vesicle population, composed of elongated, curved, and typical sombreros, and the eosinophil sombrero vesicle 3-dimensional architecture, diameter, and density remain unchanged in the extracellular matrix; (iv) free eosinophil sombrero vesicles closely associate with extracellular granules; and (v) free eosinophil sombrero vesicles also associate with externalized chromatin during eosinophil ETosis. Remarkably, eosinophil sombrero vesicles appeared on the surface of other cells, such as plasma cells. Thus, eosinophil cytolysis/ETosis can secrete intact sombrero vesicles, alongside granules, in inflamed tissues of eosinophil-associated diseases, potentially serving as propagators of eosinophil immune responses after cell death.

Eosinophil-rich granulomas, formed around tissue-trapped parasite eggs, are hallmarks of schistosomiasis mansoni, a prevalent neglected tropical disease. How eosinophils populate and affect the complex Schistosoma granulomas remains unclear. Here, we mapped eosinophils across evolutional hepatic granulomas in a mouse model and in a primary wild reservoir for human schistosomiasis in Brazil (water rat Nectomys squamipes ). With in-depth quantitative image analysis and three-dimensional histological reconstructions of entire granulomas, we find that eosinophils are spatially organized and occupy a major, peripheral niche conserved across space and time in all granuloma stages and both experimental and natural infections. Within this niche, immature and mature eosinophils coinhabit, compartmentalize their major basic protein-1 content, robustly interact with other immune cells, and secrete through piecemeal degranulation. This unveiled niche, unrelated to parasite eggs, challenges the concept of eosinophil as a “helminth killer” cell and invigorates its view as an immunoregulatory cell of the tissue microenvironment in Schistosoma granulomas.