TY - JOUR
T1 - Mouse STAT2 restricts early dengue virus replication
AU - Ashour, Joseph
AU - Morrison, Juliet
AU - Laurent-Rolle, Maudry
AU - Belicha-Villanueva, Alan
AU - Plumlee, Courtney Ray
AU - Bernal-Rubio, Dabeiba
AU - Williams, Katherine L.
AU - Harris, Eva
AU - Fernandez-Sesma, Ana
AU - Schindler, Christian
AU - García-Sastre, Adolfo
N1 - Funding Information:
This work was supported by grant U54 AI57158 (to A.G.-S.), grant AI058211 (C.S.), and grant 5R01 AI073450 (A.F.-S.) from the National Institutes of Health and by a National Institutes of Health fellowship (to M.L.-R.). We thank Megan Shaw, Estanislao Nistal-Villan, Benjamin tenOever, David Levy, and Luis Martinez-Sobrido for kindly providing plasmids. We thank Richard Cádagan for excellent technical assistance and Valmas Charalampos and Inma Barasa for helping with the statistics. We thank Domenico Tortorella for his sage advice.
PY - 2010/11/18
Y1 - 2010/11/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78349248232&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2010.10.007
DO - 10.1016/j.chom.2010.10.007
M3 - Article
C2 - 21075352
AN - SCOPUS:78349248232
SN - 1931-3128
VL - 8
SP - 410
EP - 421
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 5
ER -