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dc.contributor.authorZhu, J.-Y.
dc.contributor.authorLee, J.-G.
dc.contributor.authorvan de Leemput, J.en_US
dc.contributor.authorKane, M.A.en_US
dc.contributor.authorHan, Z.en_US
dc.date.accessioned2021-04-12T16:16:39Z
dc.date.available2021-04-12T16:16:39Z
dc.date.issued2021-03-25
dc.identifier.urihttp://hdl.handle.net/10713/15165
dc.description.abstractBackground: SARS-CoV-2 causes COVID-19 with a widely diverse disease profile that affects many different tissues. The mechanisms underlying its pathogenicity in host organisms remain unclear. Animal models for studying the pathogenicity of SARS-CoV-2 proteins are lacking. Methods: Using bioinformatic analysis, we found that 90% of the virus-host interactions involve human proteins conserved in Drosophila. Therefore, we generated a series of transgenic fly lines for individual SARS-CoV-2 genes, and used the Gal4-UAS system to express these viral genes in Drosophila to study their pathogenicity. Results: We found that the ubiquitous expression of Orf6, Nsp6 or Orf7a in Drosophila led to reduced viability and tissue defects, including reduced trachea branching as well as muscle deficits resulting in a "held-up" wing phenotype and poor climbing ability. Furthermore, muscles in these flies showed dramatically reduced mitochondria. Since Orf6 was found to interact with nucleopore proteins XPO1, we tested Selinexor, a drug that inhibits XPO1, and found that it could attenuate the Orf6-induced lethality and tissue-specific phenotypes observed in flies. Conclusions: Our study established Drosophila as a model for studying the function of SARS-CoV2 genes, identified Orf6 as a highly pathogenic protein in various tissues, and demonstrated the potential of Selinexor for inhibiting Orf6 toxicity using an in vivo animal model system. Copyright 2021, The Author(s).en_US
dc.description.sponsorshipThis work was supported, in part, by the University of Maryland Baltimore Institute for Clinical and Translational Research (UMB ICTR) COVID-19 Accelerated Translational Incubator Pilot (ATIP) grant to Dr. Han.en_US
dc.description.urihttps://doi.org/10.1186/s13578-021-00567-8en_US
dc.language.isoen_USen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofCell and Bioscience
dc.subjectSelinexoren_US
dc.subject.meshDrosophila
dc.subject.meshSARS-CoV-2--pathogenicityen_US
dc.titleFunctional analysis of SARS-CoV-2 proteins in Drosophila identifies Orf6-induced pathogenic effects with Selinexor as an effective treatmenten_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13578-021-00567-8


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