| First Author | Bills CJ | Year | 2023 |
| Journal | Emerg Microbes Infect | Volume | 12 |
| Issue | 1 | Pages | 2209208 |
| PubMed ID | 37114433 | Mgi Jnum | J:359626 |
| Mgi Id | MGI:7788521 | Doi | 10.1080/22221751.2023.2209208 |
| Citation | Bills CJ, et al. (2023) Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism. Emerg Microbes Infect 12(1):2209208 |
| abstractText | 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 (DeltaSGF or DeltaLSG) 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 DeltaSGF deletion (DeltaSGF-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 DeltaSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 DeltaSGF deletion and additional mutations in other genes). Analyses of host responses from DeltaSGF-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. |
