title: Brain inositol is a novel stimulator for promoting Cryptococcus penetration of the blood-brain barrier.
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.
authors.affiliation: Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.
authors.forename: Tong-Bao
authors.initials: TB
authors.lastname: Liu
authors.forename: Jong-Chul
authors.initials: JC
authors.lastname: Kim
authors.forename: Yina
authors.initials: Y
authors.lastname: Wang
authors.forename: Dena L
authors.initials: DL
authors.lastname: Toffaletti
authors.forename: Eliseo
authors.initials: E
authors.lastname: Eugenin
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Kee Jun
authors.initials: KJ
authors.lastname: Kim
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Xue
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000382:microbiology*; D001921:Brain / Q000378:metabolism* / Q000382:microbiology*; D002494:Central Nervous System Infections / Q000378:metabolism / Q000382:microbiology; D003453:Cryptococcosis / Q000378:metabolism / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000378:metabolism / Q000472:pathogenicity*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000378:metabolism; D007294:Inositol / Q000378:metabolism*; D008297:Male; D016919:Meningitis, Cryptococcal / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008805:Mice, Inbred A; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D057705:Transendothelial and Transepithelial Migration
chemical_list: D018960:Hyaluronan Receptors; D009004:Monosaccharide Transport Proteins; D007294:Inositol; D006820:Hyaluronic Acid