Functional analysis of SARS-CoV-2 proteins in Drosophila identifies Orf6-induced pathogenic effects with Selinexor as an effective treatment

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. Using bioinformatic analysis, we found...

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Bibliographic Details
Published in:Cell & bioscience 2021-03, Vol.11 (1), p.59-13, Article 59
Main Authors: Zhu, Jun-Yi, Lee, Jin-Gu, van de Leemput, Joyce, Lee, Hangnoh, Han, Zhe
Format: Article
Language:English
Subjects:
Analysis
Animal models
Coronaviruses
COVID-19
Disease transmission
Drosophila
Genes
Genetic aspects
Genetic engineering
Genomes
Health aspects
Infections
Insect viruses
Insects
Lethality
Localization
Microcephaly
Mitochondria
Mortality
Muscles
Pathogenicity
Phenotypes
Proteins
Respiratory diseases
Severe acute respiratory syndrome coronavirus 2
Toxicity
Trachea
Viral infections
Virulence
Zika virus
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Summary: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. 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. 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. 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.
ISSN:2045-3701
2045-3701
DOI:10.1186/s13578-021-00567-8