Unveiling the role of fungal extracellular vesicles in human infections

Fungal infections caused by species like Candida, Cryptococcus, and Paracoccidioides pose significant challenges to healthcare systems worldwide, leading to millions of deaths each year. Diagnosis and treatment of these infections are particularly difficult due to limited access to diagnostic tests and the rise of antifungal resistance. Researchers at the University of Sao Paulo examined the role of extracellular vesicles (EVs) in fungal infections, aiming to shed light on their impact on the host immune response and identify potential therapeutic targets.

Extracellular vesicles are small structures released by fungal cells that play a crucial role in facilitating interactions between the fungus and its host. Despite their importance, the complexity of fungal EVs and the lack of clinical studies on their role in human infections have made understanding their functions challenging.

To address this gap, the researchers analyzed EVs isolated from serum and urine samples of patients infected with Candida albicans, Cryptococcus neoformans, and Paracoccidioides brasiliensis. Through mass spectrometry analysis, they identified several secondary metabolites, including steroids, sphingolipids, and fatty acids, within these EVs.

Next, the researchers investigated whether these metabolites could modulate the host immune response. Their findings revealed that EVs from fungal infections induced a proinflammatory response in both murine and human macrophages. This response was characterized by increased production of cytokines such as tumor necrosis factor-α, interferon-γ, and interleukin-6, as well as elevated expression of the inducible nitric oxide synthase gene, a marker of M1 macrophage activation.

Annotations of secondary metabolites in the serum EVs of healthy individuals and patients infected by C. albicans, C. neoformans, and P. brasiliensis

Molecular networks generated by the GNPS platform (nodes with library correspondence in FBMN) and representation of the chemical structure of compounds belonging to the steroids (cholesterol and ergosterol) (A, D), sphingolipids (phytosphingosine and sphingosine) (E, H), and fatty acids (oleic acid) (I) classes. Statistical determination of the peak areas of steroids (B, C), sphingolipids (F, G), and fatty acids (J) in the serum EVs of healthy individuals and patients infected by C. albicans, C. neoformans, and P. brasiliensis. Healthy individuals were used as controls. Statistical difference: ns, p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

These results suggest that circulating EVs from patients with fungal infections play a crucial role in the pathophysiology of these diseases. By promoting a proinflammatory response, fungal EVs may contribute to the progression and severity of infection. Importantly, these findings also highlight potential targets for the development of therapies to treat systemic fungal infections.

In conclusion, this study provides valuable insights into the role of fungal EVs in human infections, paving the way for future research aimed at unraveling the mechanisms underlying fungal pathogenesis and identifying novel therapeutic strategies to combat these deadly infections.

de Rezende CP, Santos PWS, Piraine RA et al. (2024) Extracellular vesicles produced during fungal infection in humans are immunologically active. bioRXiv [online preprint]. [article]

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