title: The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice.
abstract: Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from mucormycosis. These results suggest a unique susceptibility of patients with DKA to mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections.
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
authors.forename: Mingfu
authors.initials: M
authors.lastname: Liu
authors.forename: Brad
authors.initials: B
authors.lastname: Spellberg
authors.forename: Quynh T
authors.initials: QT
authors.lastname: Phan
authors.forename: Yue
authors.initials: Y
authors.lastname: Fu
authors.forename: Yong
authors.initials: Y
authors.lastname: Fu
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Scott G
authors.initials: SG
authors.lastname: Filler
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000378:metabolism; D003920:Diabetes Mellitus; D016883:Diabetic Ketoacidosis / Q000150:complications; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009090:Mucorales / Q000378:metabolism*; D009091:Mucormycosis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III; D012233:Rhizopus / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D020096:Zygomycosis / Q000150:complications
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D008565:Membrane Proteins; C018551:glucose-regulated proteins; D007501:Iron; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse