Extracellular vesicles from Distinct <i>Histoplasma capsulatum</i> Strains Modulate Phagocyte Function and Promote Fungal Persistence

Fungal extracellular vesicles (EVs) are lipid-bilayer compartments that transport a wide range of molecules, including proteins, polysaccharides, pigments, small metabolites, lipids, and RNA. In fungal pathogens, EVs harbor virulence factors as well as antigenic determinants that modulate the host immune response. In this work, we investigated the modulatory effects of EVs released by two phenotypically and genotypically distinct strains of <i>Histoplasma capsulatum</i> (G-217B and G-184A) on bone marrow-derived macrophages (BMDMs) and bone marrow-derived dendritic cells (BMDCs). Both host cells internalized <i>H. capsulatum</i> EVs, which appeared to elicit distinct functional responses. Treatment of BMDMs with EVs from either strain (EV_HcG-184A and EV_HcG-217B) increased IL-6 production with no significant changes in IL-10 levels. In contrast, BMDCs exposed with both EVs exhibited elevated levels of IL-6 and IL-10. Although EV treatment led to increased inducible nitric oxide synthase expression in BMDMs, it did not stimulate NO production. Remarkably, both EVs reduced the metabolic activity of phagocytes. Overnight exposure to EV_HcG-217B enhanced the phagocytosis of <i>H. capsulatum</i> yeasts by BMDMs; however, the phagolysosomal fusion was not affected. Notably, in DCs, EV_HcG-217B enhanced both the uptake and the viability of G-217B yeasts. Furthermore, incubation of <i>H. capsulatum</i> with its respective EVs promoted fungal growth, suggesting a self-stimulatory mechanism that may contribute to fungal persistence within host cells. Taken together, our results support the idea that <i>H. capsulatum</i> EVs are modulators of host-pathogen interaction, influencing phagocyte function and potentially contributing to fungal virulence.