Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 211, Issue 7, Pages 1484-1497Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131092
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- Deutsche Forschungsgemeinschaft [GraKo 1121]
- Charite-Universitatsmedizin Berlin
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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 beta 2 null mice identified beta 2 integrin receptors as a master switch for NET induction. Further experiments suggested that beta 2 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 beta 2 integrin induced strong NET formation. Collectively, beta 2 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.
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