tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2023 Apr 28;2209208.
doi: 10.1080/22221751.2023.2209208. Online ahead of print. Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism
Cody J Bills[SUP] 1 [/SUP], Hongjie Xia[SUP] 1 [/SUP], John Yun-Chung Chen[SUP] 1 [/SUP], Jason Yeung[SUP] 1 [/SUP], Birte Kalveram[SUP] 1 2 [/SUP], David Walker[SUP] 3 4 [/SUP], Xuping Xie[SUP] 1 [/SUP], Pei-Yong Shi[SUP] 1 5 6 7 8 9 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) in nonstructural protein 6 (nsp6) independently acquired in Alpha and Omicron sublineages of SARS-CoV-2 augments nsp6-mediated antagonism of type-I interferon (IFN-I) signaling. Specifically, these triple deletions enhance the ability of mutant nsp6 to suppress phosphorylation of STAT1 and STAT2. A parental SARS-CoV-2 USA-WA1/2020 strain containing the nsp6 ΔSGF deletion (ΔSGF-WA1) shows reduced susceptibility to IFN-I treatment in vitro, outcompetes the parental strain in human primary airway cultures, and increases virulence in mice; however, the ΔSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 ΔSGF deletion and additional mutations in other genes). Analyses of host responses from ΔSGF-WA1-infected mice and primary airway cultures reveal activation of pathways indicative of a cytokine storm. These results provide evidence that mutations outside the Spike protein affect virus-host interactions and may alter pathogenesis of SARS-CoV-2 variants in humans.
Keywords: SARS-CoV-2; cytokine storm; interferon; nsp6; variants.
. 2023 Apr 28;2209208.
doi: 10.1080/22221751.2023.2209208. Online ahead of print. Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism
Cody J Bills[SUP] 1 [/SUP], Hongjie Xia[SUP] 1 [/SUP], John Yun-Chung Chen[SUP] 1 [/SUP], Jason Yeung[SUP] 1 [/SUP], Birte Kalveram[SUP] 1 2 [/SUP], David Walker[SUP] 3 4 [/SUP], Xuping Xie[SUP] 1 [/SUP], Pei-Yong Shi[SUP] 1 5 6 7 8 9 [/SUP]
Affiliations
- PMID: 37114433
- DOI: 10.1080/22221751.2023.2209208
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) in nonstructural protein 6 (nsp6) independently acquired in Alpha and Omicron sublineages of SARS-CoV-2 augments nsp6-mediated antagonism of type-I interferon (IFN-I) signaling. Specifically, these triple deletions enhance the ability of mutant nsp6 to suppress phosphorylation of STAT1 and STAT2. A parental SARS-CoV-2 USA-WA1/2020 strain containing the nsp6 ΔSGF deletion (ΔSGF-WA1) shows reduced susceptibility to IFN-I treatment in vitro, outcompetes the parental strain in human primary airway cultures, and increases virulence in mice; however, the ΔSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 ΔSGF deletion and additional mutations in other genes). Analyses of host responses from ΔSGF-WA1-infected mice and primary airway cultures reveal activation of pathways indicative of a cytokine storm. These results provide evidence that mutations outside the Spike protein affect virus-host interactions and may alter pathogenesis of SARS-CoV-2 variants in humans.
Keywords: SARS-CoV-2; cytokine storm; interferon; nsp6; variants.