TY - JOUR
T1 - Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease
AU - Ding, Qiang
AU - Gaska, Jenna M.
AU - Douam, Florian
AU - Wei, Lei
AU - Kim, David
AU - Balev, Metodi
AU - Heller, Brigitte
AU - Ploss, Alexander
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Tom Shenk (Princeton University) and Michael Diamond (Washington University in St. Louis) for sharing the Zika virus strains of MR766 and Dakar41671, respectively; Dr. Sergei Kotenko (Rutgers University) for providing the Ifnar−/−mice; members of the A.P. laboratory for critical discussions and comments on the manuscript; and Christina DeCoste and Katherine Rittenbach and the Molecular Biology Flow Cytometry Resource Facility, which is partially supported by the Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720. This work was supported by National Institutes of Health Grants R01 AI107301 and R21 AI117213 (to A.P.); and a grant from the Grand Health Challenge program from Princeton University and an Investigator in Pathogenesis Award by the Burroughs Wellcome Fund (to A.P.). Q.D. and L.W. are supported by New Jersey Commission on Cancer Research Postdoctoral Fellowships DHFS16PPC007 (to Q.D.) and DFHS17PPC011 (to L.W.).
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/7/3
Y1 - 2018/7/3
N2 - The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human—but not murine—cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells. Indeed, human, but not mouse, STING is subject to cleavage by proteases encoded by ZIKV, dengue virus, West Nile virus, and Japanese encephalitis virus, but not that of yellow fever virus. The protease cleavage site, located between positions 78/79 of human STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic disruption of STING increases the susceptibility of mouse—but not human—cells to ZIKV. Accordingly, expression of only mouse, not human, STING in murine STING knockout cells rescues the ZIKV suppression phenotype. STING-deficient mice, however, did not exhibit increased susceptibility, suggesting that other redundant antiviral pathways control ZIKV infection in vivo. Collectively, our data demonstrate that numerous RNA viruses evade cGAS/STING-dependent signaling and affirm the importance of this pathway in shaping the host range of ZIKV. Furthermore, our results explain—at least in part—the decreased permissivity of rodent cells to ZIKV, which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses.
AB - The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human—but not murine—cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells. Indeed, human, but not mouse, STING is subject to cleavage by proteases encoded by ZIKV, dengue virus, West Nile virus, and Japanese encephalitis virus, but not that of yellow fever virus. The protease cleavage site, located between positions 78/79 of human STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic disruption of STING increases the susceptibility of mouse—but not human—cells to ZIKV. Accordingly, expression of only mouse, not human, STING in murine STING knockout cells rescues the ZIKV suppression phenotype. STING-deficient mice, however, did not exhibit increased susceptibility, suggesting that other redundant antiviral pathways control ZIKV infection in vivo. Collectively, our data demonstrate that numerous RNA viruses evade cGAS/STING-dependent signaling and affirm the importance of this pathway in shaping the host range of ZIKV. Furthermore, our results explain—at least in part—the decreased permissivity of rodent cells to ZIKV, which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses.
KW - Antiviral immunity
KW - Flavivirus
KW - Species tropism
KW - Viral evasion
KW - Zika virus
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U2 - 10.1073/pnas.1803406115
DO - 10.1073/pnas.1803406115
M3 - Article
C2 - 29915078
AN - SCOPUS:85049359814
SN - 0027-8424
VL - 115
SP - E6310-E6318
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -