The recent outbreak of COVID-19, a respiratory disease caused by the novel coronavirus SARS-CoV-2, poses a global threat. Presently, there are no definitive drugs available to cure this potentially fatal disease. Numerous studies on protein-protein interactions have unveiled the physical association between various SARS-CoV-2 proteins and host proteins. Notably, the viral protein ORF3A has been identified to interact with the ion channel-forming protein Pannexins in host cells.

Mammals possess three subtypes of Pannexins: Panx1, Panx2, and Panx3. Panx1, in particular, releases ATP and various inflammatory molecules upon full activation. Extracellular ATP, released through Panx1, induces cell death by activating the purinergic P2X7 receptor (P2X7R). Under normal physiological conditions, Panx1 channels remain closed; however, increased cytosolic Ca2+ and various apoptotic stimuli can activate the channels, leading to heightened inflammation.

My research is aimed to comprehend the implications of the interaction between ORF3A and Panx1 in the host cell. The physical interaction between Panx1 and ORF3A has been validated through pull-down assays. Intriguingly, the transfection of ORF3A into N2A and HEK-293T cells resulted in an increased expression of Panx1 and P2X7R. Furthermore, ORF3A expression enhanced ATP release and cytotoxicity, a phenomenon mitigated by the Panx1 blocker CBX. This suggests that ORF3A activates Panx1-P2X7R-mediated inflammatory signaling, offering therapeutic potential for treating COVID-19 by targeting Panx1.

Ongoing studies aim to elucidate the ORF3A-Panx1 interaction and the subsequent signaling processes downstream.