A(H9N2) 禽流感病毒抗原变异的分子基础。,Emerging Microbes & Infections

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A(H9N2) 禽流感病毒抗原变异的分子基础。
Emerging Microbes & Infections ( IF 8.4 ) Pub Date : 2018-Nov-07 , DOI: 10.1038/s41426-018-0178-y
Thomas P Peacock _{1,

2} , William T Harvey ₃ , Jean-Remy Sadeyen ₁ , Richard Reeve ₃ , Munir Iqbal ₁

Affiliation

禽流感 A(H9N2) 病毒对全球家禽生产的威胁越来越大，并通过人畜共患感染对人类健康构成威胁，它们被认为是具有大流行潜力的病毒。家禽疫苗接种是流行国家疾病控制的关键要素，但疫苗的有效性一直受到抗原变异体出现的挑战。在这里，我们采用了多种技术的组合来研究 H9N2 抗原变异性的遗传基础，并评估免疫逃逸的不同分子机制的作用。我们系统地测试了已发表的 H9N2 单克隆抗体逃逸突变体对鸡抗血清结合的影响，确定许多没有显着影响。引入额外糖基化位点的取代是一个明显的例外，尽管这些在流行的病毒中相对罕见。为了确定导致循环病毒抗原变异的替换，我们对所有已发表的 H9 血凝素序列和抗原数据进行了综合荟萃分析。我们通过实验验证了这一统计分析，并将几个新残基分配给 H9N2 抗原位点，提供了有助于解释疫苗在现场失效并为疫苗选择决策提供信息的分子标记。我们找到了免疫逃逸替代机制重要性的证据，除了表位结构的简单调节之外，替换增加了糖基化或受体结合亲和力，对鸡抗血清结合的影响最大。这些，

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The molecular basis of antigenic variation among A(H9N2) avian influenza viruses.

Avian influenza A(H9N2) viruses are an increasing threat to global poultry production and, through zoonotic infection, to human health where they are considered viruses with pandemic potential. Vaccination of poultry is a key element of disease control in endemic countries, but vaccine effectiveness is persistently challenged by the emergence of antigenic variants. Here we employed a combination of techniques to investigate the genetic basis of H9N2 antigenic variability and evaluate the role of different molecular mechanisms of immune escape. We systematically tested the influence of published H9N2 monoclonal antibody escape mutants on chicken antisera binding, determining that many have no significant effect. Substitutions introducing additional glycosylation sites were a notable exception, though these are relatively rare among circulating viruses. To identify substitutions responsible for antigenic variation in circulating viruses, we performed an integrated meta-analysis of all published H9 haemagglutinin sequences and antigenic data. We validated this statistical analysis experimentally and allocated several new residues to H9N2 antigenic sites, providing molecular markers that will help explain vaccine breakdown in the field and inform vaccine selection decisions. We find evidence for the importance of alternative mechanisms of immune escape, beyond simple modulation of epitope structure, with substitutions increasing glycosylation or receptor-binding avidity, exhibiting the largest impacts on chicken antisera binding. Of these, meta-analysis indicates avidity regulation to be more relevant to the evolution of circulating viruses, suggesting that a specific focus on avidity regulation is required to fully understand the molecular basis of immune escape by influenza, and potentially other viruses.

更新日期：2019-01-26

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