Brain Inositol Is a Novel Stimulator for Promoting Cryptococcus Penetration of the Blood-Brain Barrier

Tong Bao Liu, Jong Chul Kim, Yina Wang, Dena L. Toffaletti, Eliseo Eugenin, John R. Perfect, Kee Jun Kim, Chaoyang Xue

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1003247
JournalPLoS Pathogens
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

Fingerprint

Cryptococcus
Inositol
Blood-Brain Barrier
Brain
Central Nervous System Infections
Fungal Meningitis
Cryptococcal Meningitis
Cryptococcus neoformans
Hyaluronic Acid
Microarray Analysis
Up-Regulation

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Brain Inositol Is a Novel Stimulator for Promoting Cryptococcus Penetration of the Blood-Brain Barrier. / Liu, Tong Bao; Kim, Jong Chul; Wang, Yina; Toffaletti, Dena L.; Eugenin, Eliseo; Perfect, John R.; Kim, Kee Jun; Xue, Chaoyang.

In: PLoS Pathogens, Vol. 9, No. 4, e1003247, 01.04.2013.

Research output: Contribution to journalArticle

Liu, Tong Bao ; Kim, Jong Chul ; Wang, Yina ; Toffaletti, Dena L. ; Eugenin, Eliseo ; Perfect, John R. ; Kim, Kee Jun ; Xue, Chaoyang. / Brain Inositol Is a Novel Stimulator for Promoting Cryptococcus Penetration of the Blood-Brain Barrier. In: PLoS Pathogens. 2013 ; Vol. 9, No. 4.
@article{c939514e69bf4c888b51a79780df77e2,
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.",
author = "Liu, {Tong Bao} and Kim, {Jong Chul} and Yina Wang and Toffaletti, {Dena L.} and Eliseo Eugenin and Perfect, {John R.} and Kim, {Kee Jun} and Chaoyang Xue",
year = "2013",
month = "4",
day = "1",
doi = "10.1371/journal.ppat.1003247",
language = "English (US)",
volume = "9",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Brain Inositol Is a Novel Stimulator for Promoting Cryptococcus Penetration of the Blood-Brain Barrier

AU - Liu, Tong Bao

AU - Kim, Jong Chul

AU - Wang, Yina

AU - Toffaletti, Dena L.

AU - Eugenin, Eliseo

AU - Perfect, John R.

AU - Kim, Kee Jun

AU - Xue, Chaoyang

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84876823618&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876823618&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1003247

DO - 10.1371/journal.ppat.1003247

M3 - Article

C2 - 23592982

AN - SCOPUS:84876823618

VL - 9

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 4

M1 - e1003247

ER -