Complement is primarily activated in the lung in a mouse model of severe COVID-19.

In vitro studies and observational human disease data suggest the complement system contributes to SARS-CoV-2 pathogenesis, although how complement dysregulation develops in severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of COVID-19, we identify significant serologic and pulmonary complement activation post-infection. We observed C3 activation in airway and alveolar epithelia, and pulmonary vascular endothelia. Our evidence suggests the alternative pathway is the primary route of complement activation, however, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia following cytokine and SARS-CoV-2 exposure. This tissue-specific complement response appears to precede lung injury and inflammation. Our results suggest that complement activation is a defining feature of severe COVID-19 in mice, agreeing with previous publications, and provide the basis for further investigation into the role of complement in COVID-19.