慢性 SARS-CoV-2 感染期间出现的新反复性氨基酸取代的意义：一项观察性研究。
The significance of recurrent de novo amino acid substitutions that emerged during chronic SARS-CoV-2 infection: an observational study.
机构信息
State Key Laboratory for Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
Division of Infectious Diseases, Department of Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
出版信息
EBioMedicine. 2024 Sep;107:105273. doi: 10.1016/j.ebiom.2024.105273. Epub 2024 Aug 14.
BACKGROUND
De novo amino acid substitutions (DNS) frequently emerge among immunocompromised patients with chronic SARS-CoV-2 infection. While previous studies have reported these DNS, their significance has not been systematically studied.
METHODS
We performed a review of DNS that emerged during chronic SARS-CoV-2 infection. We searched PubMed until June 2023 using the keywords "(SARS-CoV-2 or COVID-19) and (mutation or sequencing) and ((prolonged infection) or (chronic infection) or (long term))". We included patients with chronic SARS-CoV-2 infection who had SARS-CoV-2 sequencing performed for at least 3 time points over at least 60 days. We also included 4 additional SARS-CoV-2 patients with chronic infection of our hospital not reported previously. We determined recurrent DNS that has appeared in multiple patients and determined the significance of these mutations among epidemiologically-significant variants.
FINDINGS
A total of 34 cases were analyzed, including 30 that were published previously and 4 from our hospital. Twenty two DNS appeared in ≥3 patients, with 14 (64%) belonging to lineage-defining mutations (LDMs) of epidemiologically-significant variants and 10 (45%) emerging among chronically-infected patients before the appearance of the corresponding variant. Notably, nsp9-T35I substitution (Orf1a T4175I) emerged in all three patients with BA.2.2 infection in 2022 before the appearance of Variants of Interest that carry nsp9-T35I as LDM (EG.5 and BA.2.86/JN.1). Structural analysis suggests that nsp9-T35I substitution may affect nsp9-nsp12 interaction, which could be critical for the function of the replication and transcription complex.
INTERPRETATION
DNS that emerges recurrently in different chronically-infected patients may be used as a marker for potential epidemiologically-significant variants.
FUNDING
Theme-Based Research Scheme [T11/709/21-N] of the Research Grants Council (See acknowledgements for full list).
背景
在慢性 SARS-CoV-2 感染的免疫功能低下患者中，经常会出现新的氨基酸取代（DNS）。虽然之前的研究已经报道了这些 DNS，但它们的意义尚未得到系统研究。
方法
我们对慢性 SARS-CoV-2 感染期间出现的 DNS 进行了回顾。我们使用关键词“（SARS-CoV-2 或 COVID-19）和（突变或测序）和（（长期感染）或（慢性感染）或（长期））”在 PubMed 上进行了搜索，截至 2023 年 6 月。我们纳入了至少进行了 3 次 SARS-CoV-2 测序且至少 60 天的慢性 SARS-CoV-2 感染患者。我们还纳入了之前未报告的我院另外 4 例慢性感染 SARS-CoV-2 的患者。我们确定了出现在多个患者中的反复出现的 DNS，并确定了这些突变在具有流行病学意义的变体中的意义。
结果
共分析了 34 例病例，包括之前发表的 30 例和我院的 4 例。22 个 DNS 出现在≥3 例患者中，其中 14 个（64%）属于具有流行病学意义的变体的谱系定义突变（LDM），10 个（45%）出现在相应变体出现之前的慢性感染患者中。值得注意的是，nsp9-T35I 取代（Orf1a T4175I）在 2022 年出现具有 LDM 的 nsp9-T35I 的关注变体（如 EG.5 和 BA.2.86/JN.1）之前，出现在所有 3 例 BA.2.2 感染患者中。结构分析表明，nsp9-T35I 取代可能会影响 nsp9-nsp12 相互作用，这对于复制和转录复合物的功能可能至关重要。
解释
在不同慢性感染患者中反复出现的 DNS 可作为潜在具有流行病学意义的变体的标志物。
资助
研究资助局主题研究计划（T11/709/21-N）（详见鸣谢名单）。
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