title: A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphylatoxin C5a.
abstract: Polymorphonuclear neutrophilic granulocytes (PMN) as cellular components of innate immunity play a crucial role in the defense against systemic Candida albicans infection. To analyze stimuli that are required for PMN activity during C. albicans infection in a situation similar to in vivo, we used a human whole-blood infection model. In this model, PMN activation 10 min after C. albicans infection was largely dependent on the anaphylatoxin C5a. Most importantly, C5a enabled blood PMN to overcome filament-restricted recognition of C. albicans and allowed efficient elimination of nonfilamentous C. albicans cph1Δ/efg1Δ from blood. Major PMN effector mechanisms, including oxidative burst, release of secondary granule contents and initial fungal phagocytosis could be prevented by blocking C5a receptor signaling. Identical effects were achieved using a humanized Ab specifically targeting human C5a. Phagocytosis of C. albicans 10 min postinfection was mediated by C5a-dependent enhancement of CD11b surface expression on PMN, thus establishing the C5a-C5aR-CD11b axis as a major modulator of early anti-Candida immune responses in human blood. In contrast, phagocytosis of C. albicans by PMN 60 min postinfection occurred almost independently of C5a and mainly contributed to activation of phagocytically active PMN at later time points. Our results show that C5a is a critical mediator in human blood during C. albicans infection.
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hünniger
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany;
authors.forename: Kristin
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany;
authors.forename: Ronny
authors.initials: R
authors.lastname: Martin
authors.affiliation: Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany; Friedrich Schiller University Jena, 07743 Jena, Germany;
authors.forename: Teresa
authors.initials: T
authors.lastname: Lehnert
authors.affiliation: Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany; Friedrich Schiller University Jena, 07743 Jena, Germany;
authors.forename: Marc Thilo
authors.initials: MT
authors.lastname: Figge
authors.affiliation: Department of Internal Medicine II, University Hospital Wuerzburg, 97080 Wuerzburg, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Löffler
authors.affiliation: InflaRx GmbH, 07745 Jena, Germany;
authors.forename: Ren-Feng
authors.initials: RF
authors.lastname: Guo
authors.affiliation: InflaRx GmbH, 07745 Jena, Germany; Department of Anesthesiology and Intensive Care Therapy, Jena University Hospital, 07747 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany; and.
authors.forename: Niels C
authors.initials: NC
authors.lastname: Riedemann
authors.affiliation: Septomics Research Center, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany; and German National Reference Center for Invasive Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, 07745 Jena, Germany oliver.kurzai@hki-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D005658:Fungi / Q000276:immunology*; D006801:Humans; D009181:Mycoses / Q000276:immunology* / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D039481:CD11b Antigen; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a