Antagonism of STAT1 by Nipah virus P gene products modulates disease course but not lethal outcome in the ferret model

• Published in: Scientific reports 2019-11, Vol.9 (1), p.16710-18, Article 16710
• Main Authors: Satterfield, Benjamin A., Borisevich, Viktoriya, Foster, Stephanie L., Rodriguez, Sergio E., Cross, Robert W., Fenton, Karla A., Agans, Krystle N., Basler, Christopher F., Geisbert, Thomas W., Mire, Chad E.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/51; 14/1; 14/63; 45/70; 45/77; 45/90; 45/91; 631/326; 631/326/596/2558; Amino acids; Animals; Antagonism; Antibodies, Neutralizing - immunology; Binding Sites; Disease Models, Animal; Disease Progression; Female; Ferrets; Gene deletion; Henipavirus Infections - metabolism; Henipavirus Infections - pathology; Henipavirus Infections - virology; Humanities and Social Sciences; Interferon; multidisciplinary; Mutation; Nipah Virus - physiology; Overexpression; Phosphoproteins - genetics; Phosphoproteins - metabolism; Science; Science (multidisciplinary); Stat1 protein; STAT1 Transcription Factor - antagonists & inhibitors; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; STAT1 Transcription Factor - metabolism; Viral Proteins - genetics; Viral Proteins - metabolism; Viral Structural Proteins - genetics; Viral Structural Proteins - metabolism; Zoonoses
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-53037-0

Nipah virus (NiV) is a pathogenic paramyxovirus and zoononis with very high human fatality rates. Previous protein over-expression studies have shown that various mutations to the common N-terminal STAT1-binding motif of the NiV P, V, and W proteins affected the STAT1-binding ability of these proteins thus interfering with he JAK/STAT pathway and reducing their ability to inhibit type-I IFN signaling, but due to differing techniques it was unclear which amino acids were most important in this interaction or what impact this had on pathogenesis in vivo . We compared all previously described mutations in parallel and found the amino acid mutation Y116E demonstrated the greatest reduction in binding to STAT1 and the greatest reduction in interferon antagonism. A similar reduction in binding and activity was seen for a deletion of twenty amino acids constituting the described STAT1-binding domain. To investigate the contribution of this STAT1-binding motif in NiV-mediated disease, we produced rNiVs with complete deletion of the STAT1-binding motif or the Y116E mutation for ferret challenge studies (rNiV M -STAT1 blind ). Despite the reduced IFN inhibitory function, ferrets challenged with these rNiV M -STAT1 blind mutants had a lethal, albeit altered, NiV-mediated disease course. These data, together with our previously published data, suggest that the major role of NiV P, V, and W in NiV-mediated disease in the ferret model are likely to be in the inhibition of viral recognition/innate immune signaling induction with a minor role for inhibition of IFN signaling.