title: Histidine-rich glycoprotein protects from systemic Candida infection.
abstract: Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial proteins and peptides are becoming increasingly recognized as important effectors of innate immunity. This is illustrated further by the present investigation, demonstrating a novel antifungal role of histidine-rich glycoprotein (HRG), an abundant and multimodular plasma protein. HRG bound to Candida cells, and induced breaks in the cell walls of the organisms. Correspondingly, HRG preferentially lysed ergosterol-containing liposomes but not cholesterol-containing ones, indicating a specificity for fungal versus other types of eukaryotic membranes. Both antifungal and membrane-rupturing activities of HRG were enhanced at low pH, and mapped to the histidine-rich region of the protein. Ex vivo, HRG-containing plasma as well as fibrin clots exerted antifungal effects. In vivo, Hrg(-/-) mice were susceptible to infection by C. albicans, in contrast to wild-type mice, which were highly resistant to infection. The results demonstrate a key and previously unknown antifungal role of HRG in innate immunity.
authors.affiliation: Section of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Lund, Sweden. victoria.rydengard@med.lu.se
authors.forename: Victoria
authors.initials: V
authors.lastname: Rydengård
authors.forename: Oonagh
authors.initials: O
authors.lastname: Shannon
authors.forename: Katarina
authors.initials: K
authors.lastname: Lundqvist
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kacprzyk
authors.forename: Anna
authors.initials: A
authors.lastname: Chalupka
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
mesh_terms: D000818:Animals; D001665:Binding Sites; D002175:Candida / Q000276:immunology; D002177:Candidiasis / Q000276:immunology*; D002473:Cell Wall; D004875:Ergosterol / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D011485:Protein Binding; D011506:Proteins / Q000276:immunology* / Q000378:metabolism; D013379:Substrate Specificity; D000099053:Histidine-Rich Glycoprotein
chemical_list: D011506:Proteins; D000099053:Histidine-Rich Glycoprotein; D004875:Ergosterol
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