ORF8: A Complement evasion protein of SARS-CoV-2

A novel Coronavirus spread worldwide in December 2019 causing 69 million infections and nearly 6.9 million deaths till May 2023. Recently the WHO declared the end of emergency but these types of viruses always remain a threat to humankind and there is a paramount possibility of the emergence and re-emergence of similar viruses in the future. The presence of complement activation markers (C3b, Bb, C4d, iC3b, C3a, Ba) in the vital organs of severely hospitalized patients is one of the prominent pathological features of COVID-19. Complement is the first line of defense and during infection, it plays a significant role in tagging and eliminating viruses, bacteria, and fungi. It appears that the complement system in COVID-19 has two opposite roles in the early and late phases of infection. In the early phase, all arms of innate immunity including the complement system tried to overcome the infection, as a response virus employed complement evasion strategies and succeeded to remain unnoticed which helps in viral replication. In the later phase, defective viral clearance induces the cytokine storm, immune cell infiltration, and inflammatory response as a result of excessive complement activation, which leads to lung damage. I was interested to know about the molecular mechanism and how SARS-CoV-2 circumvents Complement – one of the ancient enzyme cascade networks of plasma proteins and cell surface-bound receptors.

      We have reported that ORF8 which is one of the 9 accessory proteins, screens the SARS-CoV-2 from immunological recognition and intervenes in its targeted elimination by complement. ORF8 is a binding partner of central complement component C3 and its metabolite (C3b, iC3b, C3 (H2O), C3d). C3b-ORF8 co-complex shield C3/C3b binding to Factor H (a cell surface/ soluble human complement regulator), serine proteases Factor B & Factor I, which eventually inhibits augmentation of complement amplification loop, a necessary step for killing SARS-CoV-2.