Coronaviruses exploit a host cysteine-aspartic protease for replication

Abstract

Highly pathogenic coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-1 vary in their transmissibility and pathogenicity. The mechanism underlying these differences remains largely unexplained. However, substantial apoptosis induced by infection of all three viruses have been documented in infected cells and patient tissues, suggesting a previously unrecognized link between apoptosis cascade and the pathogenesis of coronaviruses. In this study, I show that caspase-6, a cysteine-aspartic protease which is the central component involved in apoptosis cascade, serves as an important host factor for efficient coronavirus replication. I 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 reduces the replication of all evaluated human pathogenic coronaviruses including human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), SARS-CoV-1, MERS-CoV and SARS-CoV-2 in vitro. In human ex vivo lung tissues and human intestinal organoids, inhibition of caspase-6 limits the replication of MERS-CoV. Importantly, inhibition of caspase-6 markedly attenuates the replication of SARS-CoV-2 in infected lungs and substantially ameliorates the lung pathology, leading to significant improvement of body weight loss in SARS-CoV-2-infected golden Syrian hamsters. Similarly, inhibition of caspase-6 dramatically reduces the replication of MERS-CoV in infected lungs and improves the survival of mouse-adapted MERS-CoV (MERS-CoVMA)-infected human DPP4 knock-in (hDPP4 KI) mice. These findings are further validated with caspase-6 knockout in the hDPP4 KI mice, which shows significantly attenuated MERS-CoV replication in infected lungs in comparison to the caspase-6 intact mice. Overall, my study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.