Fig 11. Working model of EphA2-dependent migration of C. neoformans across the BBB.
C. neoformans associates directly with the luminal side of the brain endothelium and induces EphA2 phosphorylation through transactivation of CD44 bound to C. neoformans. This promotes GTPase-dependent signaling that reorganizes the actin cytoskeleton and internalizes C. neoformans via endocytotic and transcellular mechanisms that require Mpr1 and Annexin A2 (AnxA2).[18,69] Sustained EphA2 activation could weaken intercellular junctions thereby increase paracellular permeability and boost further entry of C. neoformans along with excess fluid that would lead to brain edema (indicated by dashed arrows).