Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease

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...

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Published in	Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 27; pp. E6310 - E6318
Main Authors	Ding, Qiang, Gaska, Jenna M., Douam, Florian, Wei, Lei, Kim, David, Balev, Metodi, Heller, Brigitte, Ploss, Alexander
Format	Journal Article
Language	English
Published	United States National Academy of Sciences 03.07.2018
Series	PNAS Plus
Subjects	Animals Antiviral drugs Apes Biodiversity Biological Sciences Chlorocebus aethiops Cleavage Cyclic GMP Dengue fever Disease control Disruption Encephalitis Fever Fibroblasts HEK293 Cells Host range Humans Immunity, Innate Interferon Membrane Proteins - genetics Membrane Proteins - immunology Mice Monkeys Peptide Hydrolases - genetics Peptide Hydrolases - immunology Permissivity Phenotypes PNAS Plus Primates Protease Proteases Proteinase Proteolysis Ribonucleic acid RNA RNA viruses Rodents Signal transduction Signal Transduction - genetics Signal Transduction - immunology Signaling Species Specificity Stimulators Tropism Vector-borne diseases Vero Cells Viral diseases Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - immunology Viruses West Nile virus Zika virus Zika Virus - genetics Zika Virus - immunology viral evasion Zika virus antiviral immunity species tropism flavivirus
Online Access	Get full text
ISSN	0027-8424 1091-6490 1091-6490
DOI	10.1073/pnas.1803406115

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Abstract	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.
AbstractList	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. 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.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. To shed light on the host range of Zika virus (ZIKV), we surveyed the virus’ ability to infect cells of evolutionarily diverse species. ZIKV replicates efficiently in human, great ape, Old and New World monkey, but not rodent cells. These observations correlated with ZIKV’s ability to blunt the cGAS/STING signaling pathway in all primate cells tested but not in mice. We demonstrate that an enzyme shared by many flaviviruses (NS2B3) is responsible for functionally inactivating this antiviral defense. Our results highlight the importance of the cGAS/STING pathway in shaping the host range of ZIKV, which in turn may guide the development of murine models with inheritable susceptibility to ZIKV and other flaviviruses. 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.
Author	Heller, Brigitte Ding, Qiang Douam, Florian Ploss, Alexander Wei, Lei Balev, Metodi Kim, David Gaska, Jenna M.
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/29915078$$D View this record in MEDLINE/PubMed
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Keywords	viral evasion Zika virus antiviral immunity species tropism flavivirus
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PublicationSeriesTitle	PNAS Plus
PublicationTitle	Proceedings of the National Academy of Sciences - PNAS
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PublicationYear	2018
Publisher	National Academy of Sciences
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Snippet	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... To shed light on the host range of Zika virus (ZIKV), we surveyed the virus’ ability to infect cells of evolutionarily diverse species. ZIKV replicates...
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SubjectTerms	Animals Antiviral drugs Apes Biodiversity Biological Sciences Chlorocebus aethiops Cleavage Cyclic GMP Dengue fever Disease control Disruption Encephalitis Fever Fibroblasts HEK293 Cells Host range Humans Immunity, Innate Interferon Membrane Proteins - genetics Membrane Proteins - immunology Mice Monkeys Peptide Hydrolases - genetics Peptide Hydrolases - immunology Permissivity Phenotypes PNAS Plus Primates Protease Proteases Proteinase Proteolysis Ribonucleic acid RNA RNA viruses Rodents Signal transduction Signal Transduction - genetics Signal Transduction - immunology Signaling Species Specificity Stimulators Tropism Vector-borne diseases Vero Cells Viral diseases Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - immunology Viruses West Nile virus Zika virus Zika Virus - genetics Zika Virus - immunology
Title	Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease
URI	https://www.jstor.org/stable/26511109 https://www.ncbi.nlm.nih.gov/pubmed/29915078 https://www.proquest.com/docview/2101970708 https://www.proquest.com/docview/2057115517 https://pubmed.ncbi.nlm.nih.gov/PMC6142274
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