Complement activation occurs in patients infected with MERS-CoV, SARS-CoV-1 and SARS-CoV-2, which might be involved in the pathogenesis of acute lung injury and acute respiratory distress syndrome (ARDS). In this preprint, Gao et al. identify the host complement activator MASP2 as a target of the N protein of all three viruses. In mice, lung injury induced by SARS-CoV-1 or MERS-CoV N protein was attenuated when its MASP2-binding motif was altered, when MASP2 was genetically knocked out or when the MASP2–N protein interaction was pharmacologically blocked. Preliminary data from patients treated with a blocking antibody to complement component C5a suggest a potential benefit of targeting complement in patients with COVID-19 with severe lung injury.