Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection.
Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection.
复制标题
Omicron 变体中的功能丧失突变会降低刺突蛋白表达并减弱 SARS-CoV-2 感染。
DOI：
10.1101/2023.04.17.536926
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Crocquet-Valdes,
中科院分区：
文献类型：
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作者：
Vu,MichelleN;Alvarado,RElias;Morris,DorotheaR;Lokugamage,KumariG;Zhou,Yiyang;Morgan,AngelicaL;Estes,LeahK;McLeland,AlyssaM;Schindewolf,Craig;Plante,JessicaA;Ahearn,YaniP;Meyers,WilliamM;Murray,JordanT;Crocquet-Valdes,
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.
