title: β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps.
abstract: Rodent-borne hantaviruses are emerging human pathogens that cause severe human disease. The underlying mechanisms are not well understood, as hantaviruses replicate in endothelial and epithelial cells without causing any cytopathic effect. We demonstrate that hantaviruses strongly stimulated neutrophils to release neutrophil extracellular traps (NETs). Hantavirus infection induced high systemic levels of circulating NETs in patients and this systemic NET overflow was accompanied by production of autoantibodies to nuclear antigens. Analysis of the responsible mechanism using neutrophils from β2 null mice identified β2 integrin receptors as a master switch for NET induction. Further experiments suggested that β2 integrin receptors such as complement receptor 3 (CR3) and 4 (CR4) may act as novel hantavirus entry receptors. Using adenoviruses, we confirmed that viral interaction with β2 integrin induced strong NET formation. Collectively, β2 integrin-mediated systemic NET overflow is a novel viral mechanism of immunopathology that may be responsible for characteristic aspects of hantavirus-associated disease such as kidney and lung damage.
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Raftery
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Pritesh
authors.initials: P
authors.lastname: Lalwani
authors.affiliation: Department of Nephrology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Krautkrӓmer
authors.affiliation: Department of Dermatology and Allergic Diseases, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Peters
authors.affiliation: Department of Dermatology and Allergic Diseases, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany Division of Virology, Labor Berlin Charité-Vivantes GmbH, 13353 Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hofmann
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Seeger
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Detlev H
authors.initials: DH
authors.lastname: Krüger
authors.affiliation: Institute of Medical Virology, Helmut-Ruska-Haus, Department of Pediatric Pneumology and Immunology, and Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany guenther.schoenrich@charite.de.
authors.forename: Günther
authors.initials: G
authors.lastname: Schönrich
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006476:Orthohantavirus / Q000276:immunology*; D018778:Hantavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000235:genetics / Q000276:immunology; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D018821:CD18 Antigens; D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen