Coronaviruses exploit a host cysteine-aspartic protease for replication

Abstract

Highly pathogenic coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)^1,2, Middle East respiratory syndrome coronavirus (MERS-CoV)³, and SARS-CoV-1⁴ vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture^5-7 and in patient tissues^8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that a cysteine-aspartic protease of the apoptosis cascade, caspase-6, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid (N) proteins, generating N fragments that serve as interferon (IFN) antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss of SARS-CoV-2-infected golden Syrian hamsters and improves the survival of mouse-adapted MERS-CoV (MERS-CoV_MA)-infected human DPP4 knock-in (hDPP4 KI) mice. Overall, our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.