PDF(Pubmed)
Abstract：
The receptor-binding site of influenza A virus hemagglutinin partially overlaps with major antigenic sites and constantly evolves. In this study, we observe that mutations G186D and D190N in the hemagglutinin receptor-binding site have coevolved in two recent human H3N2 clades. X-ray crystallography results show that these mutations coordinately drive the evolution of the hemagglutinin receptor binding mode. Epistasis between G186D and D190N is further demonstrated by glycan binding and thermostability analyses. Immunization and neutralization experiments using mouse and human samples indicate that the evolution of receptor binding mode is accompanied by a change in antigenicity. Besides, combinatorial mutagenesis reveals that G186D and D190N, along with other natural mutations in recent H3N2 strains, alter the compatibility with a common egg-adaptive mutation in seasonal influenza vaccines. Overall, our findings elucidate the role of epistasis in shaping the recent evolution of human H3N2 hemagglutinin and substantiate the high evolvability of its receptor-binding mode.
摘要：
甲型流感病毒血凝素的受体结合位点与主要抗原位点部分重叠并不断进化。在这项研究中,我们观察到血凝素受体结合位点的突变G186D和D190N在最近的两个人类H3N2进化枝中共同进化。X射线晶体学结果表明，这些突变协同驱动血凝素受体结合模式的进化。通过聚糖结合和热稳定性分析进一步证明了G186D和D190N之间的差异。使用小鼠和人样品的免疫和中和实验表明，受体结合模式的演变伴随着抗原性的变化。此外,组合诱变揭示了G186D和D190N，以及最近H3N2菌株中的其他自然突变，改变与季节性流感疫苗中常见的鸡蛋适应性突变的相容性。总的来说,我们的研究结果阐明了上位在塑造人类H3N2血凝素的最新进化中的作用,并证实了其受体结合模式的高度进化性.
