Joint Research Center for Human Retrovirus Infection, Kumamoto Universitygrid.274841.c, Kumamoto, Japan.
Graduate School of Medical Sciences, Kumamoto Universitygrid.274841.c, Kumamoto, Japan.
J Virol. 2022 Oct 26;96(20):e0116222. doi: 10.1128/jvi.01162-22. Epub 2022 Oct 10.
Mutations at spike protein L452 are recurrently observed in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC), including omicron lineages. It remains elusive how amino acid substitutions at L452 are selected in VOC. Here, we characterized all 19 possible mutations at this site and revealed that five mutants expressing the amino acids Q, K, H, M, and R gained greater fusogenicity and pseudovirus infectivity, whereas other mutants failed to maintain steady-state expression levels and/or pseudovirus infectivity. Moreover, the five mutants showed decreased sensitivity toward neutralization by vaccine-induced antisera and conferred escape from T cell recognition. Contrary to expectations, sequence data retrieved from the Global Initiative on Sharing All Influenza Data (GISAID) revealed that the naturally occurring L452 mutations were limited to Q, M, and R, all of which can arise from a single nucleotide change. Collectively, these findings highlight that the codon base change mutational barrier is a prerequisite for amino acid substitutions at L452, in addition to the phenotypic advantages of viral fitness and decreased sensitivity to host immunity. In a span of less than 3 years since the declaration of the coronavirus pandemic, numerous SARS-CoV-2 variants of concern have emerged all around the globe, fueling a surge in the number of cases and deaths that caused severe strain on the health care system. A major concern is whether viral evolution eventually promotes greater fitness advantages, transmissibility, and immune escape. In this study, we addressed the differential effect of amino acid substitutions at a frequent mutation site, L452 of SARS-CoV-2 spike, on viral antigenic and immunological profiles and demonstrated how the virus evolves to select one amino acid over the others to ensure better viral infectivity and immune evasion. Identifying such virus mutation signatures could be crucial for the preparedness of future interventions to control COVID-19.
刺突蛋白 L452 上的突变经常在严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的关注变体（VOC）中观察到，包括奥密克戎谱系。L452 上的氨基酸取代是如何被选择的，这仍然难以捉摸。在这里，我们对该位点的所有 19 种可能突变进行了特征描述，结果表明，表达 Q、K、H、M 和 R 氨基酸的五个突变体获得了更高的融合性和假病毒感染性，而其他突变体未能维持稳定的表达水平和/或假病毒感染性。此外，这五个突变体对疫苗诱导的抗血清的中和敏感性降低，并导致 T 细胞识别的逃逸。与预期相反，从全球共享流感数据倡议（GISAID）中检索到的序列数据表明，自然发生的 L452 突变仅限于 Q、M 和 R，所有这些都可以由单个核苷酸变化产生。总的来说，这些发现强调了密码子碱基变化突变障碍是 L452 上氨基酸取代的前提，除了病毒适应性和对宿主免疫敏感性降低的表型优势之外。自冠状病毒大流行宣布以来不到 3 年的时间里，全球出现了许多令人关注的 SARS-CoV-2 变体，导致病例和死亡人数激增，给医疗保健系统带来了严重压力。人们主要担心的是病毒进化是否最终会促进更大的适应性优势、传染性和免疫逃逸。在这项研究中，我们研究了 SARS-CoV-2 刺突蛋白 L452 上频繁突变位点的氨基酸取代对病毒抗原和免疫学特征的差异影响，并证明了病毒如何进化以选择一种氨基酸而不是其他氨基酸来确保更好的病毒感染力和免疫逃逸。确定这种病毒突变特征对于未来控制 COVID-19 的干预措施的准备工作可能至关重要。
