Abstract
Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that Cryptococcus 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 Cryptococcus traversal across the blood-brain barrier (BBB) both in an in vitro human BBB model and in in vivo 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 Cryptococcus cells, which is a ligand known to binding host CD44 receptor for their invasion. These studies suggest an inositol-dependent Cryptococcus traversal of the BBB, and support our hypothesis that utilization of host-derived inositol by Cryptococcus contributes to CNS infection.
Highlights
Cryptococcus neoformans is a basidiomycetous yeast pathogen that often causes life-threatening infections
We found that inositol promotes the traversal of Cryptococcus across the bloodbrain barrier (BBB), and such stimulation is fungal inositol transporter dependent
We identified the effects of host inositol on fungal cellular functions that contribute to the stimulation of fungal penetration of the blood-brain barrier (BBB)
Summary
Cryptococcus neoformans is a basidiomycetous yeast pathogen that often causes life-threatening infections. It causes the most common fungal infection of the central nervous system (CNS) in HIV-infected persons and may present as encephalitis, meningitis, or cerebralspace-occupying lesions [1,2,3,4,5,6]. Despite its medical importance and significant research efforts [3,8,9,10], the molecular basis of cryptococcal CNS infection and host factors affecting disease development are poorly understood, which complicates efforts for rapid diagnosis and effective treatment. There is an urgent need to understand the molecular basis of cryptococcal CNS infection to allow the discovery and development of safer and more effective antifungal drugs
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