Abstract
BackgroundSARS-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.MethodsUsing 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.ResultsWe 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.ConclusionsOur 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.
Highlights
SARS-CoV-2, the cause of coronavirus disease 2019 (COVID19), is the latest in a string of outbreaks in the human population caused by highly pathogenic coronaviruses
SARS‐CoV‐2 Orf6, Nsp6, and Orf7a transgene expression causes developmental lethality and reduced longevity in flies The SARS-CoV-2 genome encodes 28 confirmed proteins (Orf9c genetic code does not lie within the verified SARS-CoV-2 open reading frame) (Fig. 1a)
We examined all human proteins identified with high-confidence interactions with SARS-CoV-2 proteins and found that 90.13% have conserved homologs in Drosophila
Summary
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID19), is the latest in a string of outbreaks in the human population caused by highly pathogenic coronaviruses. Molecular modeling has indicated the SARS-CoV-2 receptor binding domain has a higher affinity for ACE2 compared to its SARS-CoV counterpart [6], which might contribute to its high virulence. These findings highlight the important roles specific viral genes can play, yet very little is known of the functions of individual SARS-CoV-2 proteins and the host systems they affect. SARS-CoV-2 causes COVID-19 with a widely diverse disease profile that affects many different tissues. Animal models for studying the pathogenicity of SARS-CoV-2 proteins are lacking
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