SARS‐CoV‐2 triggers complement activation through interactions with heparan sulfate

Abstract

Abstract Objectives To determine whether SARS‐CoV‐2 can trigger complement activation, the pathways that are involved and the functional significance of the resultant effect. Methods SARS‐CoV‐2 was inoculated into a human lepirudin‐anticoagulated whole blood model, which contains a full repertoire of complement factors and leukocytes that express complement receptors. Complement activation was determined by measuring C5a production with an ELISA, and pretreatment with specific inhibitors was used to identify the pathways involved. The functional significance of this was then assessed by measuring markers of C5a signalling including leukocyte C5aR1 internalisation and CD11b upregulation with flow cytometry. Results SARS‐CoV‐2 inoculation in this whole blood model caused progressive C5a production over 24 h, which was significantly reduced by inhibitors for factor B, C3, C5 and heparan sulfate. However, this phenomenon could not be replicated in cell‐free plasma, highlighting the requirement for cell surface interactions with heparan sulfate. Functional analysis of this phenomenon revealed that C5aR1 signalling and CD11b upregulation in granulocytes and monocytes was delayed and only occurred after 24 h. Conclusion SARS‐CoV‐2 is a noncanonical alternative pathway activator that progressively triggers complement activation through interactions with heparan sulfate.

Keywords

• alternative pathway
• complement
• coronavirus
• heparan sulfate
• leukocyte activation
• SARS‐CoV‐2