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

PLoS Pathogens

Kee Jun Kim¹  Jong-Chul Kim²  Eliseo Eugenin³  Chaoyang Xue³  Tong-Bao Liu⁴  Yina Wang⁴  John R. Perfect⁴  Dena L. Toffaletti⁵ 

[1] Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America;Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, United States of America;Division of Infectious Disease, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America;Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America;Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China

关键词: Cryptococcus;    Cryptococcus neoformans;    Cryptococcal meningitis;    Central nervous system;    Fungal diseases;    Yeast infections;    Phospholipids;    C;    ida albicans;   

DOI  :  10.1371/journal.ppat.1003247

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY