Early and persistent activation of complement is considered to play a key role in the
pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory
environment that might be critical for the induction and maintenance of a severe inflammatory
response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of
infection and shifting their state of activation towards an inflammatory phenotype. It precedes
pathophysiological milestone events like the cytokine storm, progressive endothelial injury
triggering microangiopathy, and further complement activation, and causes an acute respiratory
distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have
shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease
severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that
lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and
CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and
C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2
binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP
using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement
activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein
confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the
MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of
our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we
suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for
the treatment of severe COVID-19.
Keywords: COVID-19; SARS-CoV-2; complement system; innate immunity; lectin pathway.
Reference
Ali, Y. M., Ferrari, M., Lynch, N. J., Yaseen, S., Dudler, T., Gragerov, S., ... & Schwaeble, W. J. (2021). Lectin pathway mediates complement activation by SARS-CoV-2 proteins. Frontiers in immunology, 12, 2645.