SARS-CoV-2 hijacks host CD55, CD59 and Factor H to impair antibody-dependent complement-mediated lysis

The complement system is a vital anti-microbial defence mechanism against circulating pathogens. Excessive complement activation can have deleterious outcomes for the host and is consequently tightly modulated by a set of membrane-associated and fluid-phase regulators of complement activation (RCAs). Here, we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks host cellular RCA members CD55 and CD59 and serum-derived Factor H (FH) to resist antibody-dependent complement-mediated lysis triggered by immunised human sera. Blockage of the biological functions of virion-associated CD55 and CD59 and competition of FH recruitment with functionally inactive recombinant FH-derived short consensus repeats SCR18-20 restore SARS-CoV-2 complement sensitivity in a synergistic manner. Moreover, complement-mediated virolysis is dependent on classical pathway activation and does not occur in the absence of virus-specific antibodies. Altogether, our findings present an intriguing immune escape mechanism that provides novel insights into the immunopathology observed in severe coronavirus disease 2019 (COVID-19).

补体系统（complement system）是抵御循环病原体的关键抗微生物防御机制。补体过度激活会对宿主产生有害影响，因此该过程会受到一系列膜结合型及液相补体激活调节因子（regulators of complement activation, RCAs）的严格调控。本研究证实，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）会劫持宿主细胞的补体激活调节因子成员CD55、CD59以及血清来源的补体因子H（Factor H, FH），以抵御免疫人血清触发的抗体依赖性补体介导的病毒裂解。阻断病毒粒子结合的CD55与CD59的生物学功能，并通过功能失活的重组补体因子H来源的短同源重复序列SCR18-20竞争性抑制补体因子H的招募，可协同恢复SARS-CoV-2对补体介导裂解的敏感性。此外，补体介导的病毒裂解依赖于补体经典激活途径的激活，且仅在存在病毒特异性抗体时才会发生。综上，本研究揭示了一种新颖的免疫逃逸机制，为阐释重型新型冠状病毒肺炎（COVID-19）的免疫病理特征提供了全新视角。