Cryptococci at the brain gate: break and enter or use a Trojan horse?

Abstract

The mechanism by which Cryptococcus neoformans invades the central nervous system is fundamental for understanding pathogenesis because cryptococcosis commonly presents as meningoencephalitis. There is evidence for both direct invasion of the endothelial cells lining the brain vasculature and a "Trojan horse" mechanism whereby cryptococci enter the central nervous system after macrophage ingestion. However, in this issue of the JCI, Shi et al. use intravital microscopy to reveal that brain invasion by C. neoformans follows a capillary microembolic event. They find that after suddenly stopping in brain capillaries, cryptococci cross into the central nervous system in a process that is urease dependent, requires viability, and involves cellular deformation. This observation provides evidence for direct brain invasion by C. neoformans, but a consideration of all the currently available evidence suggests a role for both direct and phagocyte-associated invasion. Hence, the remarkable neurotropism of C. neoformans may have more than one mechanism.

Figure 1. Mechanisms by which C. neoformans has been posited to enter the central nervous system.

C. neoformans can travel in blood in either free or phagocytic cell–associated form. Free yeast forms in blood could originate from exocytosis from phagocytic cells or perhaps transmigration from primary infection areas such as the lung. (i) The Trojan horse mechanism. C. neoformans reaches the brain inside an infected phagocytic cell that transports it across from the lumen of a brain capillary to the central nervous system. (ii) Direct transcytosis. C. neoformans reaches the brain by direct transmigration of capillary endothelium.