title: Involvement of human CD44 during Cryptococcus neoformans infection of brain microvascular endothelial cells.
abstract: Pathogenic yeast Cryptococcus neoformans causes devastating cryptococcal meningoencephalitis. Our previous studies demonstrated that C. neoformans hyaluronic acid was required for invasion into human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier. In this report, we demonstrate that C. neoformans hyaluronic acid interacts with CD44 on HBMEC. Our results suggest that HBMEC CD44 is a primary receptor during C. neoformans infection, based on the following observations. First, anti-CD44 neutralizing antibody treatment was able to significantly reduce C. neoformans association with HBMEC. Second, C. neoformans association was considerably impaired using either CD44-knock-down HBMEC or C. neoformans hyaluronic acid-deficient strains. Third, overexpression of CD44 in HBMEC increased their association activity towards C. neoformans. Fourth, confocal microscopic images showed that CD44 was enriched at and around the C. neoformans association sites. Fifth, upon C. neoformans and HBMEC engagement, a subpopulation of CD44 and actin translocated to the host membrane rafts. Our results highlight the interactions between C. neoformans hyaluronic acid and host CD44 and the dynamic results of these interactions, which may represent events during the adhesion and entry of C. neoformans at HBMEC membrane rafts.
authors.affiliation: Division of Hematology-Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. ajong@chla.usc.edu
authors.forename: Ambrose
authors.initials: A
authors.lastname: Jong
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wu
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Shackleford
authors.forename: Kyung J
authors.initials: KJ
authors.lastname: Kwon-Chung
authors.forename: Yun C
authors.initials: YC
authors.lastname: Chang
authors.forename: Han-Min
authors.initials: HM
authors.lastname: Chen
authors.forename: Yannan
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Sheng-He
authors.initials: SH
authors.lastname: Huang
mesh_terms: D001921:Brain / Q000098:blood supply; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000737:chemistry / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism* / Q000382:microbiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D008590:Meningoencephalitis / Q000382:microbiology
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid