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.

SARS-CoV-2病毒，即COVID-19的病原体，正经历着持续的变异。本研究采用了一种整合的方法，结合流行病学、病毒基因组测序、临床表型分型和实验验证，以定位具有临床意义的突变。我们鉴定出35个反复出现的变异株，其中一些与严重程度相关的临床表型有关。一种包含Nsp1编码区（Δ500-532）缺失的变异株在超过20%的测序样本中被发现，并且与感染患者的更高RT-PCR循环阈值和更低的血清IFN-β水平相关联。该位点的缺失变异株在全球37个国家被发现，由临床样本分离出的或通过反向遗传学构建的含有相关缺失的Nsp1的病毒，同样在感染Calu-3细胞中诱导出较低的IFN-β反应。综合来看，我们的病毒学监测描绘了反复出现的遗传多样性，并确定了在Nsp1中的具有生物学和临床意义的突变，这些突变共同可能有助于分子诊断和药物设计。