Drosophila has been used to functionally characterize 2 genes of the original SARS-CoV virus, HCoV-SARS\3a and HCoV-SARS\M. Either gene, when expressed in the developing fly eye, produces an easily scored phenotype in the adult eye. This has allowed genetic screens for interacting genes.
SARS-CoV-2 infection results in the coronavirus disease termed COVID-19. COVID-19 first appeared in human populations in late 2019, spread rapidly, and became a worldwide pandemic in 2020. The SARS-CoV-2 genome has been compared to the SARS-CoV-1 genome; see Naqvi et al., 2020 (pubmed:32544429).
The SARS-CoV-2\ORF3a gene, homologous to the 3a gene in SAR-CoV-1, has been introduced into flies. Neural expression has the most deleterious effects, including reduced lifespan and reduced locomotor function. Chloroquine was shown to ameliorate these pathogenic phenotypes.
The GAL4-UAS system in Drosophila has been used to characterize 12 viral proteins deemed most likely to instigate pathogenic host interactions (see FBrf0248509). Three genes showed the most profound effects: SARS-CoV-2\ORF6, SARS-CoV-2\ORF7a, and SARS-CoV-2\nsp6. Ubiquitous expression of these three viral genes leads to reduced viability and tissue defects, reduced trachea branching, poor climbing ability, and reduced mitochondria in muscles. Using the SARS-CoV-2\ORF6 model, efficacy of the pharmaceutical Selinexor was assessed.
Drosophila genes orthologous to human genes reported as components of SARS-CoV-2/human interactome have been identified. Among these are Dmel\Ance and Dmel\Ance-3, moderate-scoring orthologs of the human gene ACE2, which has been identified as a functional receptor for SARS-CoV viruses. Neural or muscle-specific RNAi-mediated knockdown of Dmel\Ance or Dmel\Ance-3 is sufficient to trigger motor dysfunction similar to those observed in fly models of neuromuscular disease, suggesting that ACE2 interference may play a role in COVID-19-related neuromuscular disturbances (Herrera, et al. 2023; pmid:37495086; FBrf0257445).
SARS-CoV-2\nsp8 has been extensively characterized in the fly system; it has been shown to interact with with several human candidates, most prominently with the ATE1 arginyltransferase, to induce actin arginylation and cytoskeletal disorganization.
A comprehensive Drosophila COVID-19 resource (DCR) has been created (Guichard et al., 2023; pubmed:37480566; FBrf0257460); it consists of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of human proteins that interact with SARS-CoV-2.
[updated Jan. 2024 by FlyBase; FBrf0222196]
The genomes of SARS-CoV viruses are comprised of a single-stranded positive-sense RNA. The genome of SARS-CoV-2 shares about 89% sequence identity with other CoVs (Naqvi et al., 2020; pubmed:32544429).
The human gene ACE2 encodes a protein belonging to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronavirus HCoV-NL63 and the human severe acute respiratory syndrome coronaviruses, SARS-CoV and SARS-CoV-2, the latter is the causative agent of coronavirus disease-2019 (COVID-19). [provided by RefSeq, Nov 2020]
Two to many (2 human to multiple Drosophila); the additional orthologous human gene is ACE. ACE2 has three moderate-scoring Drosophila orthologs, Acer, Ance, and Ance-3, and several additional low-scoring orthologs.
One to one: 1 human gene to 1 Drosophila gene.
Moderate-scoring ortholog of human ACE2 and ACE.
Moderate-scoring ortholog of human ACE2 and ACE.
Moderate-scoring ortholog of human ACE2 and ACE.
High-scoring ortholog of human ATE1 (1 Drosophila to 1 human).
