期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：37
DOI：10.1073/pnas.2204717119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
A hallmark of the COVID-19 pandemic has been the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that both increased transmission and improved immune evasion. Each variant possesses mutations throughout its genome, but little is known about their effect on pathogenesis. Specifically, we are interested in the accessory genes of SARS-CoV-2, which have been shown to affect viral pathogenesis through interference with the host innate immune response. In this work, we identify accessory genes that are responsible for pathogenesis in vivo and investigate the effect of variant nonspike genes on replication and disease in mice. This work identifies accessory genes as key drivers of pathogenesis and highlights the effect of nonspike genes on replication and pathogenesis.
The ongoing COVID-19 pandemic is a major public health crisis. Despite the development and deployment of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pandemic persists. The continued spread of the virus is largely driven by the emergence of viral variants, which can evade the current vaccines through mutations in the spike protein. Although these differences in spike are important in terms of transmission and vaccine responses, these variants possess mutations in the other parts of their genome that may also affect pathogenesis. Of particular interest to us are the mutations present in the accessory genes, which have been shown to contribute to pathogenesis in the host through interference with innate immune signaling, among other effects on host machinery. To examine the effects of accessory protein mutations and other nonspike mutations on SARS-CoV-2 pathogenesis, we synthesized both viruses possessing deletions in the accessory genes as well as viruses where the WA-1 spike is replaced by each variant spike gene in a SARS-CoV-2/WA-1 infectious clone. We then characterized the in vitro and in vivo replication of these viruses and compared them to both WA-1 and the full variant viruses. Our work has revealed that the accessory proteins contribute to SARS-CoV-2 pathogenesis and the nonspike mutations in variants can contribute to replication of SARS-CoV-2 and pathogenesis in the host. This work suggests that while spike mutations may enhance receptor binding and entry into cells, mutations in accessory proteins may alter clinical disease presentation.
