Affiliation:
1. Molecular Virology Laboratory, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40 Dublin 2, Ireland
Abstract
Human coronavirus 229E (HCoV-229E) is associated with upper respiratory tract infections and generally causes mild respiratory symptoms. HCoV-229E infection can cause cell death, but the molecular pathways that lead to virus-induced cell death as well as the interplay between viral proteins and cellular cell death effectors remain poorly characterized for HCoV-229E. Studying how HCoV-229E and other common cold coronaviruses interact with and affect cell death pathways may help to understand its pathogenesis and compare it to that of highly pathogenic coronaviruses. Here, we report that the main protease (Mpro) of HCoV-229E can cleave gasdermin D (GSDMD) at two different sites (Q29 and Q193) within its active N-terminal domain to generate fragments that are now unable to cause pyroptosis, a form of lytic cell death normally executed by this protein. Despite GSDMD cleavage by HCoV-229E Mpro, we show that HCoV-229E infection still leads to lytic cell death. We demonstrate that during virus infection caspase-3 cleaves and activates gasdermin E (GSDME), another key executioner of pyroptosis. Accordingly, GSDME knockout cells show a significant decrease in lytic cell death upon virus infection. Finally, we show that HCoV-229E infection leads to increased lytic cell death levels in cells expressing a GSDMD mutant uncleavable by Mpro (GSDMD Q29A+Q193A). We conclude that GSDMD is inactivated by Mpro during HCoV-229E infection, preventing GSDMD-mediated cell death, and point to the caspase-3/GSDME axis as an important player in the execution of virus-induced cell death. In the context of similar reported findings for highly pathogenic coronaviruses, our results suggest that these mechanisms do not contribute to differences in pathogenicity among coronaviruses. Nonetheless, understanding the interactions of common cold-associated coronaviruses and their proteins with the programmed cell death machineries may lead to new clues for coronavirus control strategies.
Reference68 articles.
1. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020). The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol., 5, 536–544.
2. Coronavirus: Epidemiology, genome replication and the interactions with their hosts;Shi;Virol. Sin.,2016
3. Human Coronavirus-229E, -OC43, -NL63, and -HKU1 (Coronaviridae);Liu;Encycl. Virol.,2021
4. Epidemiologic clues to SARS origin in China;Xu;Emerg. Infect. Dis.,2004
5. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans;Lauber;mBio,2012