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The Cryptococcus neoformans capsule polysaccharide glucuronoxylomannan stimulates endothelial barrier permeability and the activation of Src and RhoA
Author(s) -
Khan Mahrukh,
Buttan Sagar,
Masri Abigail,
Martinez Luis,
Dores Michael Robert
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06441
Subject(s) - adherens junction , microbiology and biotechnology , rhoa , internalization , signal transduction , stress fiber , cryptococcus neoformans , biology , proto oncogene tyrosine protein kinase src , tight junction , chemistry , focal adhesion , cadherin , cell , biochemistry
The human pathogenic yeast Cryptococcus neoformans is capable of crossing the blood brain barrier (BBB), causing over 220,000 cases of fungal meningitis annually. The BBB is comprised of specialized endothelial cells that control the flow of nutrients, signaling molecules and pharmacological agents into the brain. We have identified a novel mechanism for C. neoformans endothelial barrier disruption through the shedding of its capsule polysaccharide glucuronoxylomannan (GXM). GXM stimulates the breakdown of adherens junctions between endothelial cells and stimulates actin stress‐fiber formation, however the molecular mechanisms that control these cellular responses are not known. GXM is proposed to activate toll like receptors expressed on the surface of endothelial cells. Here we demonstrate that exposure of human brain endothelial cells (HBECs) to GXM induces the activation and internalization of TLR‐2 and TLR‐4. In addition, GXM stimulation leads to the activation of Src kinase, a signaling factor that is known to stimulate VE‐cadherin internalization and adherens junction disruption. We show that treatment of HBECs with GXM activates RhoA, a signaling effector that regulates actin stress fiber formation. Our current research seeks to identify new components of these signaling pathways and to determine whether inhibition of these signaling pathways can prevent GXM‐mediated endothelial barrier permeability. Support or Funding Information NIH NIAID: 1R01AI145559‐01A1