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Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection.
Vu, Michelle N; Alvarado, R Elias; Morris, Dorothea R; Lokugamage, Kumari G; Zhou, Yiyang; Morgan, Angelica L; Estes, Leah K; McLeland, Alyssa M; Schindewolf, Craig; Plante, Jessica A; Ahearn, Yani P; Meyers, William M; Murray, Jordan T; Crocquet-Valdes, Patricia A; Weaver, Scott C; Walker, David H; Russell, William K; Routh, Andrew L; Plante, Kenneth S; Menachery, Vineet.
Affiliation
  • Vu MN; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Alvarado RE; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Morris DR; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, United States.
  • Lokugamage KG; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Zhou Y; Pediatrics, University of Texas Medical Branch, Galveston, TX, United States.
  • Morgan AL; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Estes LK; Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States.
  • McLeland AM; Pathology, University of Texas Medical Branch, Galveston, TX, United States.
  • Schindewolf C; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Plante JA; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Ahearn YP; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Meyers WM; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Murray JT; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, United States.
  • Crocquet-Valdes PA; World Reference Center of Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, United States.
  • Weaver SC; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Walker DH; Pathology, University of Texas Medical Branch, Galveston, TX, United States.
  • Russell WK; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Routh AL; Pathology, University of Texas Medical Branch, Galveston, TX, United States.
  • Plante KS; Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.
  • Menachery V; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, United States.
bioRxiv ; 2023 Jul 10.
Article in En | MEDLINE | ID: mdl-37131784
SARS-CoV-2 Omicron variants emerged in 2022 with >30 novel amino acid mutations in the spike protein alone. While most studies focus on receptor binding domain changes, mutations in the C-terminus of S1 (CTS1), adjacent to the furin cleavage site, have largely been ignored. In this study, we examined three Omicron mutations in CTS1: H655Y, N679K, and P681H. Generating a SARS-CoV-2 triple mutant (YKH), we found that the mutant increased spike processing, consistent with prior reports for H655Y and P681H individually. Next, we generated a single N679K mutant, finding reduced viral replication in vitro and less disease in vivo. Mechanistically, the N679K mutant had reduced spike protein in purified virions compared to wild-type; spike protein decreases were further exacerbated in infected cell lysates. Importantly, exogenous spike expression also revealed that N679K reduced overall spike protein yield independent of infection. Although a loss-of-function mutation, transmission competition demonstrated that N679K had a replication advantage in the upper airway over wild-type SARS-CoV-2 in hamsters, potentially impacting transmissibility. Together, the data show that N679K reduces overall spike protein levels during Omicron infection, which has important implications for infection, immunity, and transmission.

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2023 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2023 Document type: Article Affiliation country: Country of publication: