Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation

Abstract

Excessive inflammatory responses contribute to the pathogenesis and lethality of highly pathogenic human coronaviruses, but the underlying mechanism remains unclear. In this study, the N proteins of highly pathogenic human coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were found to bind MASP-2, a key serine protease in the lectin pathway of complement activation, resulting in excessive complement activation by potentiating MBL-dependent MASP-2 activation, and the deposition of MASP-2, C4b, activated C3 and C5b-9. Aggravated inflammatory lung injury was observed in mice infected with adenovirus expressing the N protein. Complement hyperactivation was also observed in SARS-CoV-2-infected patients. Either blocking the N protein:MASP-2 interaction, MASP-2 depletion or suppressing complement activation can significantly alleviate N protein-induced complement hyperactivation and lung injury in vitro and in vivo. Altogether, these data suggested that complement suppression may represent a novel therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.

The role of SARS-CoV-2 nucleocapsid protein in antiviral immunity and vaccine development

“…Serum N-protein level is correlated with a COVID-19 patient's inflammatory response, tissue damage, coagulation, and disease severity [ 19–21 ]. Extracellular SARS-CoV-2 N-protein also contributes to inflammation by regulating complement and it has been described that COVID-19 patients show complement hyperactivation [ 22 , 23 ]. The N-proteins from SARS-CoV, MERS-CoV, and SARS-CoV-2 recruit and activate mannose-binding protein-associated serine protease 2 (MASP-2), a key factor in the lectin pathway of complement activation.…”

The complement system in preeclampsia: a review of its activation and endothelial injury in the triad of COVID-19 infection and HIV-associated preeclampsia

“…These findings suggest that complement activation elevates pathology in COVID-19. Gao et al [24] observed secreted nucleoprotein (N protein) dimers of SARS-COV-2 that activate mannan-binding lectin-associated serine protease 2 (MASP-2), which is the activating enzyme of the LP, leading to the synthesis of C3 convertase and MAC formation. Additionally, an attempt to block MASP-2 and N protein interactions results in lung injury.…”

“…Gao et al [24] found remnants of complement components C3, C4, MAC, and mannose-binding lectin in alveolar epithelial cells, inflammatory cells, pneumocytes, and alveolar spaces in patients who died of COVID-19. Furthermore, they reported increased serum C5a levels in patients with COVID-19.…”

How much (evil) intelligence can be encoded by 30 kb?

“…When immune complexes with virus specific antibodies are formed, the classical pathway is also activated. Deposition of C3 and C4 on the SARS-CoV-2 virion may lead to their neutralization, but N protein of SARS-CoV2 was found to activate MBL-associated serine protease (MASP)-2, leading to the aberrant complement activation and deposition of MASP-2 and C4 in the lung tissue of severely affected COVID-19 patients (Gao et al 2022 ). The spike protein of the virus has high affinity to heparan sulphate, competing with C3b-regulatory factor H. This may sustain activation of the alternative pathway removing the inhibitory effects of factor H on C3 (Lo et al 2022 ).…”