Cryptococcus neoformans and the EGFR Puzzle: Uncovering a Novel Mechanism for Blood-Brain Barrier Crossing

Abstract Cryptococcus neoformans, a significant fungal pathogen, causes cryptococcal meningitis with high mortality. The mechanisms facilitating its invasion of the central nervous system (CNS) remain inadequately elucidated. The epidermal growth factor receptor (EGFR) assumes a pivotal role in pathogen-host interactions, yet its role in cryptococcal traversal of the blood-brain barrier (BBB) remains insufficiently characterized. Using an in vitro model of the BBB constructed from mouse brain microvascular endothelial cells (MBMECs), it has been observed that EGFR expression significantly increases during the invasion of C. neoformans. The silencing of EGFR markedly diminishes the pathogen’s capacity to penetrate the BBB. Further research has identified that the conversion of pro-HB-EGF to HB-EGF, mediated by Mpr1/ADAM, triggers the activation of EGFR, a key event in the translocation process. The inhibition of this pathway using ADAM inhibitors, such as TAPI-1, not only prevents the upregulation of HB-EGF but also strengthens the integrity of the BBB and reduces the efficiency of cryptococcal translocation. These findings suggest that targeting the EGFR signaling pathway and metalloproteinase activity could be a promising strategy in developing treatments for cryptococcal meningitis.