tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2022 Sep 13;119(37):e2204717119.
doi: 10.1073/pnas.2204717119. Epub 2022 Aug 30.
SARS-CoV-2 variant spike and accessory gene mutations alter pathogenesis
Marisa E McGrath[SUP] 1 [/SUP], Yong Xue[SUP] 2 [/SUP], Carly Dillen[SUP] 1 [/SUP], Lauren Oldfield[SUP] 2 [/SUP], N Assad-Garcia[SUP] 2 [/SUP], Jayshree Zaveri[SUP] 2 [/SUP], Natasha Singh[SUP] 2 [/SUP], Lauren Baracco[SUP] 1 [/SUP], Louis J Taylor[SUP] 1 [/SUP], Sanjay Vashee[SUP] 2 [/SUP], Matthew B Frieman[SUP] 1 3 [/SUP]
Affiliations
Abstract
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.
Keywords: SARS-CoV-2; coronavirus; mouse; pathogenesis; variant.
. 2022 Sep 13;119(37):e2204717119.
doi: 10.1073/pnas.2204717119. Epub 2022 Aug 30.
SARS-CoV-2 variant spike and accessory gene mutations alter pathogenesis
Marisa E McGrath[SUP] 1 [/SUP], Yong Xue[SUP] 2 [/SUP], Carly Dillen[SUP] 1 [/SUP], Lauren Oldfield[SUP] 2 [/SUP], N Assad-Garcia[SUP] 2 [/SUP], Jayshree Zaveri[SUP] 2 [/SUP], Natasha Singh[SUP] 2 [/SUP], Lauren Baracco[SUP] 1 [/SUP], Louis J Taylor[SUP] 1 [/SUP], Sanjay Vashee[SUP] 2 [/SUP], Matthew B Frieman[SUP] 1 3 [/SUP]
Affiliations
- PMID: 36040867
- DOI: 10.1073/pnas.2204717119
Abstract
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.
Keywords: SARS-CoV-2; coronavirus; mouse; pathogenesis; variant.