Journal Article

Enhanced complement activation and MAC formation accelerates severe COVID-19

Qin, Xuebin, Tomlinson, Stephen, Halperin, Jose A., Wang, Chenxiao, Khatun, Mst Shamima, Liu, Shumei, Chen, Zheng, Kolls, Jay K., Islamuddin, Mohammad, Maness, Nicholas J., Blair, Robert V., Xiao, Mark T., Qian, Chaosi, Ellsworth, Calder R.

2024

Overview

Emerging evidence indicates that activation of complement system leading to the formation of the membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3 −/− ; 2. C7 −/− ; and 3. Cd59ab −/− ) to evaluate the role of complement in severe COVID-19 pathogenesis. C3 deficient mice lack a key common component of all three complement activation pathways and are unable to generate C3 and C5 convertases. C7 deficient mice lack a complement protein needed for MAC formation. Cd59ab deficient mice lack an important inhibitor of MAC formation. We also used anti-C5 antibody to block and evaluate the therapeutic potential of inhibiting MAC formation. We demonstrate that inhibition of complement activation (in C3 −/− ) and MAC formation (in C3 −/− . C7 −/− , and anti-C5 antibody) attenuates severe COVID-19; whereas enhancement of MAC formation ( Cd59ab −/− ) accelerates severe COVID-19. The degree of MAC but not C3 deposits in the lungs of C3 −/− , C7 −/− mice, and Cd59ab −/− mice as compared to their control mice is associated with the attenuation or acceleration of SARS-CoV-2-induced disease. Further, the lack of terminal complement activation for the formation of MAC in C7 deficient mice protects endothelial dysfunction, which is associated with the attenuation of diseases and pathologic changes. Our results demonstrated the causative effect of MAC in severe COVID-19 and indicate a potential avenue for modulating the complement system and MAC formation in the treatment of severe COVID-19.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Activation analysis / Animals / Antibodies / Attenuation / Biochemistry / Biomedical and Life Sciences / Biomedicine / CD59 Antigens - genetics / CD59 Antigens - immunology / CD59 Antigens - metabolism / Cell Biology / Complement / Complement activation / Complement Activation - immunology / Complement C3 - genetics / Complement C3 - immunology / Complement C3 - metabolism / Complement C5 - antagonists & inhibitors / Complement C5 - immunology / Complement C5 - metabolism / Complement component C3 / Complement component C5 / Complement Membrane Attack Complex - immunology / Complement Membrane Attack Complex - metabolism / Complement system / COVID-19 / COVID-19 - immunology / COVID-19 - pathology / COVID-19 - virology / COVID-19 infection / Disease control / Disease Models, Animal / Humans / Life Sciences / Membrane attack complex / Mice / Mice, Inbred C57BL / Mice, Knockout / Original / Original Article / Pathogenesis / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / therapeutics