title: Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis.
abstract: Patients with diabetic ketoacidosis (DKA) are uniquely predisposed to mucormycosis, an angioinvasive fungal infection with high mortality. Previously, we demonstrated that Rhizopus invades the endothelium via binding of fungal CotH proteins to the host receptor GRP78. Here, we report that surface expression of GRP78 is increased in endothelial cells exposed to physiological concentrations of β-hydroxy butyrate (BHB), glucose, and iron that are similar to those found in DKA patients. Additionally, expression of R. oryzae CotH was increased within hours of incubation with DKA-associated concentrations of BHB, glucose, and iron, augmenting the ability of R. oryzae to invade and subsequently damage endothelial cells in vitro. BHB exposure also increased fungal growth and attenuated R. oryzae neutrophil-mediated damage. Further, mice given BHB developed clinical acidosis and became extremely susceptible to mucormycosis, but not aspergillosis, while sodium bicarbonate reversed this susceptibility. BHB-related acidosis exerted a direct effect on both GRP78 and CotH expression, an effect not seen with lactic acidosis. However, BHB also indirectly compromised the ability of transferrin to chelate iron, as iron chelation combined with sodium bicarbonate completely protected endothelial cells from Rhizopus-mediated invasion and damage. Our results dissect the pathogenesis of mucormycosis during ketoacidosis and reinforce the importance of careful metabolic control of the acidosis to prevent and manage this infection.
authors.forename: Teclegiorgis
authors.initials: T
authors.lastname: Gebremariam
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Mingfu
authors.initials: M
authors.lastname: Liu
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.forename: Samuel
authors.initials: S
authors.lastname: French
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: D020155:3-Hydroxybutyric Acid / Q000633:toxicity; D000818:Animals; D016883:Diabetic Ketoacidosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009091:Mucormycosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D012233:Rhizopus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D017693:Sodium Bicarbonate / Q000627:therapeutic use*; D014774:Virulence / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005656:Fungal Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D017693:Sodium Bicarbonate; D007501:Iron; D005947:Glucose; D020155:3-Hydroxybutyric Acid