title: Combined action of type I and type III interferon restricts initial replication of severe acute respiratory syndrome coronavirus in the lung but fails to inhibit systemic virus spread.
abstract: STAT1-deficient mice are more susceptible to infection with severe acute respiratory syndrome coronavirus (SARS-CoV) than type I interferon (IFN) receptor-deficient mice. We used mice lacking functional receptors for both type I and type III IFN (double knockout, dKO) to evaluate the possibility that type III IFN plays a decisive role in SARS-CoV protection. We found that viral peak titres in lungs of dKO and STAT1-deficient mice were similar, but significantly higher than in wild-type mice. The kinetics of viral clearance from the lung were also comparable in dKO and STAT1-deficient mice. Surprisingly, however, infected dKO mice remained healthy, whereas infected STAT1-deficient mice developed liver pathology and eventually succumbed to neurological disease. Our data suggest that the failure of STAT1-deficient mice to control initial SARS-CoV replication efficiently in the lung is due to impaired type I and type III IFN signalling, whereas the failure to control subsequent systemic viral spread is due to unrelated defects in STAT1-deficient mice.
authors.affiliation: Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany.|Department of Virology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Tanel
authors.initials: T
authors.lastname: Mahlakõiv
authors.affiliation: Institute of Virology, University of Bonn Medical Center, 53127 Bonn, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ritz
authors.affiliation: Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany.|Department of Virology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Mordstein
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Department of Molecular and Cell Biology, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Marta L
authors.initials: ML
authors.lastname: DeDiego
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Department of Molecular and Cell Biology, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Enjuanes
authors.affiliation: Institute of Virology, University of Bonn Medical Center, 53127 Bonn, Germany.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Müller
authors.affiliation: Institute of Virology, University of Bonn Medical Center, 53127 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
authors.affiliation: Department of Virology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
mesh_terms: D000818:Animals; D007370:Interferon Type I / Q000276:immunology*; D007372:Interferons / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D007372:Interferons