BACKGROUND: 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.