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DDX3 is exploited by Arenaviruses to suppress type I interferons and favor their replication

View ORCID ProfileMaría Eugenia Loureiro, Andre Luiz Zorzetto-Fernandes, Sheli Radoshitzky, Xiaoli Chi, Simone Dallari, Nuha Marooki, Psylvia Lèger, Sabrina Foscaldi, Sonia Sharma, Nora López, Juan Carlos de la Torre, Sina Bavari, Elina Zúñiga
doi: https://doi.org/10.1101/224725
María Eugenia Loureiro
1Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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  • ORCID record for María Eugenia Loureiro
Andre Luiz Zorzetto-Fernandes
1Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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Sheli Radoshitzky
2Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA.
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Xiaoli Chi
2Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA.
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Simone Dallari
1Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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Nuha Marooki
1Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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Psylvia Lèger
1Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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Sabrina Foscaldi
4Centro de Virología Animal, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
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Sonia Sharma
3La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
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Nora López
4Centro de Virología Animal, Instituto de Ciencia y Tecnología Dr. César Milstein, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
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Juan Carlos de la Torre
5The Scripps Research Institute, Department of Immunology and Microbiology, La Jolla, CA, USA.
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Sina Bavari
2Molecular and Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA.
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Elina Zúñiga
1Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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  • For correspondence: eizuniga@ucsd.edu
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ABSTRACT

Several arenaviruses cause hemorrhagic fever (HF) diseases that are associated with high morbidity and mortality in humans. Accordingly, HF arenaviruses have been listed as top-priority emerging diseases for which countermeasures are urgently needed. Because arenavirus nucleoprotein (NP) plays critical roles in both virus multiplication and immune-evasion, we used an unbiased proteomic approach to identify NP-interacting proteins in human cells. DDX3, a DEAD-box ATP-dependent-RNA-helicase, interacted with NP in both NP-transfected and virus-infected cells. Importantly, DDX3 deficiency compromised the propagation of both Old and New World arenaviruses, including the HF arenaviruses Lassa and Junin viruses. The DDX3 role in promoting arenavirus multiplication correlated with both a previously un-recognized DDX3 contribution to type I interferon suppression in arenavirus infected cells and a positive effect of DDX3 on viral RNA synthesis. Our results uncover novel mechanisms used by arenavirus to exploit the host machinery and subvert immunity, singling out DDX3 as a potential host target for developing new therapies against highly pathogenic arenaviruses.

AUTHOR SUMMARY Arenaviruses include severe clinical pathogens causing hemorrhagic fevers and have been recently incorporated by the World Health Organization in a list of critical emerging diseases for which additional research and identification of clinical targets is urgently required. A better understanding of how viral proteins interact with host cellular factors to favor arenavirus multiplication can illuminate novel pipelines on therapeutic strategies. Here we demonstrated that the ATP-dependent RNA helicase DDX3 interacted with the arenavirus nucleoprotein, which displays fundamental functions in different steps of the viral-cycle. Our work also revealed an unexpected new biology on the role that DDX3 might play during viral infections. In sharp contrast to previous studies showing DDX3 enhancement of IFN-I induction, we demonstrated that DDX3 suppressed IFN-I production at late time points after arenavirus infection, contributing to a DDX3 pro-viral effect. We also showed that early after infection, DDX3 pro-viral role was IFN-I independent and was mediated by DDX3 facilitation of viral RNA synthesis without affecting RNA translation. Altogether, our study established DDX3 as a critical host interacting partner of the arenavirus nucleoprotein and demonstrated two previously unrecognized DDX3-dependent strategies by which these deadly viruses exploit the host cellular machinery and suppress immunity.

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Posted November 25, 2017.
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DDX3 is exploited by Arenaviruses to suppress type I interferons and favor their replication
María Eugenia Loureiro, Andre Luiz Zorzetto-Fernandes, Sheli Radoshitzky, Xiaoli Chi, Simone Dallari, Nuha Marooki, Psylvia Lèger, Sabrina Foscaldi, Sonia Sharma, Nora López, Juan Carlos de la Torre, Sina Bavari, Elina Zúñiga
bioRxiv 224725; doi: https://doi.org/10.1101/224725
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DDX3 is exploited by Arenaviruses to suppress type I interferons and favor their replication
María Eugenia Loureiro, Andre Luiz Zorzetto-Fernandes, Sheli Radoshitzky, Xiaoli Chi, Simone Dallari, Nuha Marooki, Psylvia Lèger, Sabrina Foscaldi, Sonia Sharma, Nora López, Juan Carlos de la Torre, Sina Bavari, Elina Zúñiga
bioRxiv 224725; doi: https://doi.org/10.1101/224725

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