Pillar 4
Functional Genomics & Structure-Function of VOCs

Plants, insects, and invertebrates defend against virus infections by using an RNA based system, called RNA interference or RNAi. RNAi uses small pieces of the viral genome, termed small interfering RNAs (siRNAs) to target and destroy infectious viral genomes by using a protein that cleaves RNA, called Argonaute. In vertebrates, including humans, Argonaute proteins regulate cellular processes, but their role in antiviral defences has remained unverified and controversial. This work provides clear evidence that one of the human Argonaute proteins, Argonaute 2, has antiviral activity against SARS-CoV-2, the virus that causes COVID-19. Unlike in insects, where many siRNAs are generated from each viral genome using a protein called Dicer, the RNAi activity against SARS-CoV-2 uses a specific virus-derived siRNA that is not produced by Dicer and targets viral RNAs for cleavage where they are made. Importantly, Argonaute 2 has potent antiviral against multiple coronaviruses.  Further studies will determine the source of the viral siRNAs and develop strategies to harness this as a pan-coronavirus antiviral therapy.

Dr. Wilson’s lab provided the Argonaute-2-knockout cells in which this activity was first identified, and some of the mechanistic work was done by members of the Wilson and Kumar Labs in collaboration with Darryl Falzarano at VIDO.

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The RNA interference effector protein Argonaute 2 functions as a restriction factor against SARS-CoV-2. Joaquin Lopez-Orozco, Nowell Fayad, Juveriya Qamar Khan, Alberto Felix-Lopez, Mohamed Elaish, Megha Rohamare, Maansi Sharma, Darryl Falzarano, Jerry Pelletier, Joyce Wilson, Tom C. Hobman, Anil Kumar. Journal of Molecular Biology. 2023.08.15.168170; https://www.sciencedirect.com/science/article/abs/pii/S0022283623002577?via%3Dihub