β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps

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 neutrop...

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Veröffentlicht in:The Journal of experimental medicine Jg. 211; H. 7; S. 1485
Hauptverfasser: Raftery, Martin J, Lalwani, Pritesh, Krautkrӓmer, Ellen, Peters, Thorsten, Scharffetter-Kochanek, Karin, Krüger, Renate, Hofmann, Jörg, Seeger, Karl, Krüger, Detlev H, Schönrich, Günther
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 30.06.2014
Schlagworte:
Adenoviridae
Animals
Autoantibodies - genetics
Autoantibodies - immunology
CD18 Antigens - genetics
CD18 Antigens - immunology
CHO Cells
Cricetinae
Cricetulus
Female
Hantavirus - immunology
Hantavirus Infections - genetics
Hantavirus Infections - immunology
Hantavirus Infections - pathology
Humans
Integrin alphaXbeta2 - genetics
Integrin alphaXbeta2 - immunology
Kidney Diseases - genetics
Kidney Diseases - immunology
Kidney Diseases - pathology
Kidney Diseases - virology
Lung Diseases - genetics
Lung Diseases - immunology
Lung Diseases - pathology
Lung Diseases - virology
Macrophage-1 Antigen - genetics
Macrophage-1 Antigen - immunology
Male
Mice
Mice, Mutant Strains
Neutrophils - immunology
Neutrophils - pathology
ISSN:1540-9538, 1540-9538
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-2
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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20131092