title: CotH3 mediates fungal invasion of host cells during mucormycosis.
abstract: Angioinvasion is a hallmark of mucormycosis. Previously, we identified endothelial cell glucose-regulated protein 78 (GRP78) as a receptor for Mucorales that mediates host cell invasion. Here we determined that spore coat protein homologs (CotH) of Mucorales act as fungal ligands for GRP78. CotH proteins were widely present in Mucorales and absent from noninvasive pathogens. Heterologous expression of CotH3 and CotH2 in Saccharomyces cerevisiae conferred the ability to invade host cells via binding to GRP78. Homology modeling and computational docking studies indicated structurally compatible interactions between GRP78 and both CotH3 and CotH2. A mutant of Rhizopus oryzae, the most common cause of mucormycosis, with reduced CotH expression was impaired for invading and damaging endothelial cells and CHO cells overexpressing GRP78. This strain also exhibited reduced virulence in a diabetic ketoacidotic (DKA) mouse model of mucormycosis. Treatment with anti-CotH Abs abolished the ability of R. oryzae to invade host cells and protected DKA mice from mucormycosis. The presence of CotH in Mucorales explained the specific susceptibility of DKA patients, who have increased GRP78 levels, to mucormycosis. Together, these data indicate that CotH3 and CotH2 function as invasins that interact with host cell GRP78 to mediate pathogenic host-cell interactions and identify CotH as a promising therapeutic target for mucormycosis.
authors.forename: Teclegiorgis
authors.initials: T
authors.lastname: Gebremariam
authors.forename: Mingfu
authors.initials: M
authors.lastname: Liu
authors.forename: Guanpingsheng
authors.initials: G
authors.lastname: Luo
authors.forename: Vincent
authors.initials: V
authors.lastname: Bruno
authors.forename: Quynh T
authors.initials: QT
authors.lastname: Phan
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Scott G
authors.initials: SG
authors.lastname: Filler
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
mesh_terms: D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology; D016466:CHO Cells; D003412:Cricetulus; D016883:Diabetic Ketoacidosis / Q000276:immunology / Q000382:microbiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000382:microbiology; D005656:Fungal Proteins / Q000502:physiology*; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009091:Mucormycosis / Q000382:microbiology*; D011485:Protein Binding; D012233:Rhizopus / Q000472:pathogenicity / Q000502:physiology*; D012441:Saccharomyces cerevisiae; D017386:Sequence Homology, Amino Acid; D014774:Virulence
chemical_list: D000908:Antibodies, Fungal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005656:Fungal Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse