• Drosophila, a powerful model to study virus-host interactions and pathogenicity in the fight against SARS-CoV-2

      van de Leemput, Joyce; Han, Zhe (Springer Nature, 2021-06-13)
      The COVID-19 pandemic is having a tremendous impact on humanity. Although COVID-19 vaccines are showing promising results, they are not 100% effective and resistant mutant SARS-CoV-2 strains are on the rise. To successfully fight against SARS-CoV-2 and prepare for future coronavirus outbreaks, it is essential to understand SARS-CoV-2 protein functions, their host interactions, and how these processes convey pathogenicity at host tissue, organ and systemic levels. In vitro models are valuable but lack the physiological context of a whole organism. Current animal models for SARS-CoV-2 research are exclusively mammals, with the intrinsic limitations of long reproduction times, few progeny, ethical concerns and high maintenance costs. These limitations make them unsuitable for rapid functional investigations of virus proteins as well as genetic and pharmacological screens. Remarkably, 90% of the SARS-CoV-2 virus-host interacting proteins are conserved between Drosophila and humans. As a well-established model system for studying human diseases, the fruit fly offers a highly complementary alternative to current mammalian models for SARS-CoV-2 research, from investigating virus protein function to developing targeted drugs. Herein, we review Drosophila's track record in studying human viruses and discuss the advantages and limitations of using fruit flies for SARS-CoV-2 research. We also review studies that already used Drosophila to investigate SARS-CoV-2 protein pathogenicity and their damaging effects in COVID-19 relevant tissues, as well as studies in which the fly was used as an efficient whole animal drug testing platform for targeted therapeutics against SARS-CoV-2 proteins or their host interacting pathways.
    • Functional analysis of SARS-CoV-2 proteins in Drosophila identifies Orf6-induced pathogenic effects with Selinexor as an effective treatment

      Zhu, J.-Y.; Lee, J.-G.; van de Leemput, J.; Kane, M.A.; Han, Z. (Springer Nature, 2021-03-25)
      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. Copyright 2021, The Author(s).