Involvement of CD146 in the Cryptococcus neoformans adhesion and infection of brain endothelial cells.

Cryptococcal meningitis is a common and refractory central nervous system (CNS) infection with high mortality and disability. For Cryptococcus neoformans (C. neoformans) to penetrate the CNS, it first adheres to and breaches the blood‒brain barrier (BBB). Here, we explored the roles of CD146, an adhesion molecule expressed on the surface of brain microvascular endothelial cells (BMECs), in cryptococcal vascular adhesion and BBB invasion. Following cryptococcal infection, we observed a reduction in CD146 expression in BMECs, which was at least partially mediated by metalloproteinase-9. Once overexpressed on BMECs, CD146 increased C. neoformans adhesion; in contrast, CD146 knockout decreased the attachment of fungi to endothelial cells in vitro. Unexpectedly, CD146 knockout failed to reduce fungal infection in the brain following intravascular instillation of C. neoformans. However, the anti-CD146 antibody AA98 significantly increased the fungemia (spleen CFU), suggesting that CD146 may be involved in the early adhesion and invasion of Cryptococcus into cerebral vessels. AA98, however, failed to extend the survival of C. neoformans infected mice. These results suggest that CD146 may play dispensable roles in the C. neoformans brain infection.