Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response. A study of Lin et al.

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532) was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-β levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-β responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.

引发新型冠状病毒肺炎（COVID-19）的严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）正处于持续变异之中。本研究采用流行病学调查、病毒基因组测序、临床表型分析与实验验证相结合的整合研究策略，定位具有临床重要性的病毒突变位点。本研究共鉴定出35种复现变异株，其中部分变异株与疾病严重程度相关的临床表型存在关联。其中一株变异株在非结构蛋白1（Nsp1）编码区存在Δ500-532片段缺失，该变异株在本研究的测序样本中占比超过20%，且与感染患者更高的RT-PCR循环阈值以及更低的血清干扰素-β（IFN-β）水平相关。该位点的缺失变异株已在全球37个国家被检出；从临床样本中分离的病毒，或通过反向遗传学技术构建的携带Nsp1相关缺失突变的重组病毒，在感染Calu-3细胞后均可诱导更低水平的IFN-β应答。综上，本研究通过病毒学监测明确了复现出现的病毒遗传多样性特征，并鉴定出Nsp1中兼具生物学与临床重要性的突变位点，上述发现可为分子诊断及药物研发提供参考依据。