Brain Inositol Is a Novel Stimulator for Promoting <i>Cryptococcus</i> Penetration of the Blood-Brain Barrier

<div><p><i>Cryptococcus neoformans</i> is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of <i>Cryptococcus</i> infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that <i>Cryptococcus</i> has a sophisticated system for the acquisition of inositol from the environment suggests that host inositol utilization may contribute to the development of cryptococcal meningitis. In this study, we found that inositol plays an important role in <i>Cryptococcus</i> traversal across the blood-brain barrier (BBB) both in an <i>in vitro</i> human BBB model and in <i>in vivo</i> animal models. The capacity of inositol to stimulate BBB crossing was dependent upon fungal inositol transporters, indicated by a 70% reduction in transmigration efficiency in mutant strains lacking two major inositol transporters, Itr1a and Itr3c. Upregulation of genes involved in the inositol catabolic pathway was evident in a microarray analysis following inositol treatment. In addition, inositol increased the production of hyaluronic acid in <i>Cryptococcus</i> cells, which is a ligand known to binding host CD44 receptor for their invasion. These studies suggest an inositol-dependent <i>Cryptococcus</i> traversal of the BBB, and support our hypothesis that utilization of host-derived inositol by <i>Cryptococcus</i> contributes to CNS infection.</p>