Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510000, China.
Cell Host Microbe. 2019 Jun 12;25(6):836-844.e5. doi: 10.1016/j.chom.2019.04.013. Epub 2019 May 28.
Egg-based seasonal influenza vaccines are the major preventive countermeasure against influenza virus. However, their effectiveness can be compromised when antigenic changes arise from egg-adaptive mutations on influenza hemagglutinin (HA). The L194P mutation is commonly observed in egg-based H3N2 vaccine seed strains and significantly alters HA antigenicity. An approach to prevent L194P would therefore be beneficial. We show that emergence of L194P during egg passaging can be impeded by preexistence of a G186V mutation, revealing strong incompatibility between these mutations. X-ray structures illustrate that individual G186V and L194P mutations have opposing effects on the HA receptor-binding site (RBS), and when both G186V and L194P are present, the RBS is severely disrupted. Importantly, wild-type HA antigenicity is maintained with G186V, but not L194P. Our results demonstrate that these epistatic interactions can be used to prevent the emergence of mutations that adversely alter antigenicity during egg adaptation.
基于鸡蛋的季节性流感疫苗是预防流感病毒的主要手段。然而，当流感血凝素 (HA) 发生因适应鸡蛋而产生的抗原变化时，其有效性可能会受到影响。L194P 突变在基于鸡蛋的 H3N2 疫苗种株中很常见，并且显著改变了 HA 的抗原性。因此，采取预防 L194P 的方法将是有益的。我们表明，通过预先存在 G186V 突变，可以阻止 L194P 在鸡蛋传代过程中的出现，这揭示了这两种突变之间存在很强的不兼容性。X 射线结构表明，单独的 G186V 和 L194P 突变对 HA 受体结合位点 (RBS) 有相反的影响，当同时存在 G186V 和 L194P 时，RBS 会受到严重破坏。重要的是，G186V 存在时保持了野生型 HA 的抗原性，但 L194P 不存在。我们的结果表明，这些上位性相互作用可用于预防在鸡蛋适应过程中因改变抗原性而产生的不利突变的出现。
