Open AccessIdentification of Genes from the Fungal Pathogen Cryptococcus neoformans Related to Transmigration into the Central Nervous System
Author(s) -
Hsiang-Kuang Tseng,
Chang-Pan Liu,
Michael Price,
Ambrose Jong,
Jui-Chih Chang,
Dena L. Toffaletti,
Marisol T. Betancourt,
Aubrey E. Frazzitta,
Wen-Long Cho,
John R. Perfect
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0045083
Subject(s) - biology , cryptococcus neoformans , mutant , central nervous system , mutation , gene , microbiology and biotechnology , genetics , neuroscience
Background A mouse brain transmigration assessment (MBTA) was created to investigate the central nervous system (CNS) pathogenesis of cryptococcal meningoencephalitis. Methodology/Principal Findings Two cryptococcal mutants were identified from a pool of 109 pre-selected mutants that were signature-tagged with the nourseothricin acetyltransferase (NAT) resistance cassette. These two mutants displayed abnormal transmigration into the central nervous system. One mutant displaying decreased transmigration contains a null mutation in the putative FNX1 gene, whereas the other mutant possessing a null mutation in the putative RUB1 gene exhibited increased transmigration into the brain. Two macrophage adhesion-defective mutants in the pool, 12F1 and 3C9, showed reduced phagocytosis by macrophages, but displayed no defects in CNS entry suggesting that transit within macrophages (the “Trojan horse” model of CNS entry) is not the primary mechanism for C. neoformans migration into the CNS in this MBTA. Conclusions/Significance This research design provides a new strategy for genetic impact studies on how Cryptococcus passes through the blood-brain barrier (BBB), and the specific isolated mutants in this assay support a transcellular mechanism of CNS entry.