The COVID-19 pandemic has resulted in millions of deaths and ongoing illnesses, driving scientists to find new ways to understand how viruses enter and reprogram human cells. To tackle this challenge, researchers have developed a toolkit using fruit flies (Drosophila) to study key SARS-CoV-2 genes and their interactions with human proteins.
Led by Annabel Guichard and Ethan Bier from the University of California San Diego and Shenzhao Lu, Oguz Kanca, Shinya Yamamoto, and Hugo Bellen from Baylor College of Medicine and Texas Children’s Hospital, the multi-institutional collaboration created the Drosophila COVID Resource (DCR) to streamline the assessment of viral proteins and their interactions with human proteins.
The DCR comprises various fruit fly lines that produce the 29 known SARS-CoV-2 proteins and more than 230 crucial human targets. Additionally, it includes over 300 fly strains for studying the function of human viral targets. By using the genetic tools available in fruit flies, the researchers aim to facilitate a global analysis of SARS-CoV-2 interactions with human cells at various levels, leading to the development of new therapeutic strategies.
During their experiments, the scientists observed that nine out of ten expressed SARS-CoV-2 proteins resulted in wing defects in adult flies. These defects can provide insights into how viral proteins affect host proteins, disrupting essential cellular processes to favor the virus.
A notable finding was that NSP8, one of the viral proteins, acted as a hub, coordinating with other NSPs in a mutually reinforcing manner. NSP8 also had strong interactions with five out of 24 candidate human binding proteins. Notably, one of these proteins, called “ATE1,” plays a role in adding the amino acid arginine to other proteins, altering their functions. Elevated levels of arginine-modified actin were observed in fly cells with both NSP8 and ATE1, leading to the formation of ring-like structures similar to those seen in human cells infected with SARS-CoV-2.
Interestingly, when flies were given drugs that inhibit the activity of the human ATE1 enzyme, the effects of NSP8 were significantly reduced, suggesting a potential pathway for new therapeutics.
The researchers refer to their method as a “fly-to-bedside” resource, and these initial findings are promising for drug screening. Eight other NSPs also showed distinctive phenotypes, paving the way for identifying additional drug candidates.
Ultimately, these discoveries may not only aid in the development of new antiviral formulations but also provide insights into the causes of long-COVID symptoms and strategies for future treatments.