Zhu Jun-Yi, Lee Jin-Gu, Wang Guanglei, Duan Jianli, van de Leemput Joyce, Lee Hangnoh, Yang Wendy Wenqiao, Han Zhe
Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Baltimore, MD, 21201, USA.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Baltimore, MD, 21201, USA.
Commun Biol. 2024 Dec 3;7(1):1609. doi: 10.1038/s42003-024-07307-x.
A few years into the COVID-19 pandemic, the SARS-CoV-2 Omicron strain rapidly becomes and has remained the predominant strain. To date, Omicron and its subvariants, while more transmittable, appear to cause less severe disease than prior strains. To study the cause of this reduced pathogenicity we compare SARS-CoV-2 ancestral Nsp6 with Nsp6-Omicron, which we have previously identified as one of the most pathogenic viral proteins. Here, through ubiquitous expression in Drosophila, we show that ancestral Nsp6 causes both structural and functional damage to cardiac, muscular, and tracheal (lung) tissue, whereas Nsp6-Omicron has minimal effects. Moreover, we show that ancestral Nsp6 dysregulates the glycolysis pathway and disrupts mitochondrial function, whereas Nsp6-Omicron does not. Through validation in mouse primary cardiomyocytes, we find that Nsp6-induced dysregulated glycolysis underlies the cardiac dysfunction. Together, the results indicate that the amino acid changes in Omicron might hinder its interaction with host proteins thereby minimizing its pathogenicity.
在新冠疫情爆发几年后，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的奥密克戎毒株迅速成为并一直是主要毒株。迄今为止，奥密克戎及其亚变体虽然传播性更强，但似乎比先前的毒株导致的疾病严重程度更低。为了研究这种致病性降低的原因，我们将SARS-CoV-2原始核衣壳蛋白6（Nsp6）与奥密克戎Nsp6进行了比较，我们之前已将后者确定为最具致病性的病毒蛋白之一。在这里，通过在果蝇中的广泛表达，我们发现原始Nsp6会对心脏、肌肉和气管（肺）组织造成结构和功能损伤，而奥密克戎Nsp6的影响极小。此外，我们表明原始Nsp6会使糖酵解途径失调并破坏线粒体功能，而奥密克戎Nsp6则不会。通过在小鼠原代心肌细胞中的验证，我们发现Nsp6诱导的糖酵解失调是心脏功能障碍的基础。总之，这些结果表明奥密克戎中的氨基酸变化可能会阻碍其与宿主蛋白的相互作用，从而将其致病性降至最低。
