Extracellular vesicles produced during fungal infection in humans are immunologically active

Of the known 1.5 million fungal species, Candida spp., Cryptococcus spp., and Paracoccidioides spp. are the main pathogenic species causing serious diseases with almost two million annual deaths. The diagnosis and treatment of fungal infections are challenging since of the limited access to diagnostic tests and the emergence of antifungal resistance. Extracellular vesicles (EVs) promote the interactions of fungal cells with other organisms and play an important role in the pathogen–host relationship. Owing to the complexity of fungal EVs and the lack of clinical studies on their roles in human infections, we studied the EVs from the serum and urine samples of patients with fungal infections caused by Candida albicans , Cryptococcus neoformans , and Paracoccidioides brasiliensis and determined their roles. Steroids, sphingolipids, and fatty acids were identified as the main secondary metabolites via mass spectrometry analysis. We asked whether these metabolites in EVs could play roles in modulating the host immune response. Our findings revealed the polarization of the proinflammatory profile in murine and human macrophages, with the increased production of cytokines, such as the tumor necrosis factor-α, interferon-γ, and interleukin-6, and an increased expression of the inducible nitric oxide synthase gene, a M1 response marker. Therefore, circulating EVs from patients with fungal infections are likely involved in the disease pathophysiology. Our findings provide insights into the roles of EVs in fungal infections in clinical samples and in vitro, suggesting possible targets for systemic mycoses therapy.