title: Mouse STAT2 restricts early dengue virus replication.
abstract: Dengue virus encodes several interferon antagonists. Among these the NS5 protein binds STAT2, a necessary component of the type I interferon signaling pathway, and targets it for degradation. We now demonstrate that the ability of dengue NS5 to associate with and degrade STAT2 is species specific. Thus, NS5 is able to bind and degrade human STAT2, but not mouse STAT2. This difference was exploited to demonstrate, absent manipulation of the viral genome, that NS5-mediated IFN antagonism is essential for efficient virus replication. Moreover, we demonstrate that differences in NS5 mediated binding and degradation between human and mouse STAT2 maps to a region within the STAT2 coiled-coil domain. By using STAT2(-/-) mice, we also demonstrate that mouse STAT2 restricts early dengue virus replication in vivo. These results suggest that overcoming this restriction through transgenic mouse technology may help in the development of a long-sought immune-competent mouse model of dengue virus infection.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ashour
authors.forename: Juliet
authors.initials: J
authors.lastname: Morrison
authors.forename: Maudry
authors.initials: M
authors.lastname: Laurent-Rolle
authors.forename: Alan
authors.initials: A
authors.lastname: Belicha-Villanueva
authors.forename: Courtney Ray
authors.initials: CR
authors.lastname: Plumlee
authors.forename: Dabeiba
authors.initials: D
authors.lastname: Bernal-Rubio
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Williams
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003716:Dengue Virus / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C096041:NS5 protein, flavivirus; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C494085:Stat2 protein, mouse; D017361:Viral Nonstructural Proteins; D007372:Interferons