Amino Acid Residue 217 in the Hemagglutinin Glycoprotein Is a Key Mediator of Avian Influenza H7N9 Virus Antigenicity.
Amino Acid Residue 217 in the Hemagglutinin Glycoprotein Is a Key Mediator of Avian Influenza H7N9 Virus Antigenicity.
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DOI：
10.1128/jvi.01627-18
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发表时间：
2019-01-01
影响因子：
5.4
通讯作者：
Iqbal M
中科院分区：
文献类型：
--
作者：
Chang P;Sealy JE;Sadeyen JR;Iqbal M
在家禽和野鸟中传播的H7N9禽流感病毒继续进化并获得重要的表型变化。病毒血凝素（HA）糖蛋白的突变可以调节病毒抗原性，并促进病毒逃避天然或疫苗诱导的免疫。这项研究的重点是确定H7N9 HA中的进化标志物，这些标志物可以驱动基于抗体的免疫逃逸。为了实现这一点，我们繁殖的低致病性H7N9病毒的存在下，来自雪貂感染相同的病毒株（同源抗血清）的多克隆抗血清。这个选择过程重复了10次。第5次传代后回收的病毒HA基因序列显示，病毒容易在三个不同的氨基酸位置（A125 T、A151 T和L217 Q）获得突变。对这些突变的进一步功能分析证实，HA中残基217处的突变负责介导H7N9病毒免疫学特性的变化。禽流感病毒不断进化和获得突变，促进抗原漂移和毒力变化。2017年，低致病性H7N9禽流感病毒在中国进化为高致病性表型。低致病性和高致病性病毒株的比较抗原分析显示出明显的变异性。为了鉴定可能与H7N9病毒中的抗原变化相关的残基，我们在同源雪貂抗血清存在下连续传代病毒。对能够克服抗血清中和能力的子代病毒进行测序。分析表明，紧急免疫逃逸病毒早在第5代就在血凝素（HA）糖蛋白中含有突变A125 T、A151 T和L217 Q，这些突变持续到第10代。结果显示，H7N9病毒HA中的单一突变L217Q分别导致雪貂和鸡抗血清的血凝抑制（HI）效价降低23倍和8倍。进一步分析表明，这种变化也导致了低致病性和高致病性H7N9病毒之间的抗原差异，从而在其抗原多样性中发挥了重要作用。因此，H7N9病毒中氨基酸位置217处的进化变化可以作为疫苗种子匹配和选择期间病毒抗原多样性的遗传标记。本研究中使用的体外免疫逃逸突变体选择方法也有助于预测自然感染或免疫动物中出现的抗原变体。在家禽和野鸟中传播的H7N9禽流感病毒继续进化并获得重要的表型变化。病毒血凝素（HA）糖蛋白的突变可以调节病毒抗原性，并促进病毒逃避天然或疫苗诱导的免疫。这项研究的重点是确定H7N9 HA中的进化标志物，这些标志物可以驱动基于抗体的免疫逃逸。为了实现这一点，我们繁殖的低致病性H7N9病毒的存在下，来自雪貂感染相同的病毒株（同源抗血清）的多克隆抗血清。这个选择过程重复了10次。第5次传代后回收的病毒HA基因序列显示，病毒容易在三个不同的氨基酸位置（A125 T、A151 T和L217 Q）获得突变。对这些突变的进一步功能分析证实，HA中残基217处的突变负责介导H7N9病毒免疫学特性的变化。
Avian influenza H7N9 viruses circulating in poultry and wild birds continue to evolve and acquire important phenotypic changes. Mutations to the virus hemagglutinin (HA) glycoprotein can modulate virus antigenicity and facilitate virus escape from natural or vaccine-induced immunity. The focus of this study was to identify evolutionary markers in the HA of H7N9 that drive escape from antibody-based immunity. To achieve this, we propagated low-pathogenicity H7N9 virus in the presence of polyclonal antiserum derived from ferrets infected with the same strain of virus (homologous antiserum). This selection process was repeated 10 times. The HA gene sequences of viruses recovered after the fifth passage showed that the viruses readily acquired mutations at three different amino acid positions (A125T, A151T, and L217Q). Further functional analysis of these mutations confirmed that the mutation at residue 217 in the HA was responsible for mediating changes to the immunological properties of the H7N9 virus. Avian influenza viruses continue to evolve and acquire mutations that facilitate antigenic drift and virulence change. In 2017, low-pathogenicity H7N9 avian influenza viruses evolved to a high-pathogenicity phenotype in China. Comparative antigenic analysis of the low- and high-pathogenicity virus strains showed marked variability. In order to identify residues that may be linked to the antigenic change among the H7N9 viruses, we serially passaged the viruses in the presence of homologous ferret antiserum. Progeny viruses able to overcome the neutralizing capacity of the antiserum were sequenced. The analysis showed that the emergent immune escape viruses contained mutations A125T, A151T, and L217Q in the hemagglutinin (HA) glycoprotein as early as passage 5 and that these mutations persisted until passage 10. The results revealed that a single mutation, L217Q, in the HA of H7N9 virus led to 23- and 8-fold reductions in hemagglutination inhibition (HI) titer with ferret and chicken antisera, respectively. Further analysis showed that this change also contributed to antigenic differences between the low- and high-pathogenicity H7N9 viruses, thus playing a major role in their antigenic diversification. Therefore, evolutionary changes at amino acid position 217 in the H7N9 viruses can serve as a genetic marker for virus antigenic diversity during vaccine seed matching and selection. The in vitro immune escape mutant selection method used in this study could also aid in the prediction of emerging antigenic variants in naturally infected or immunized animals. IMPORTANCE Avian influenza H7N9 viruses circulating in poultry and wild birds continue to evolve and acquire important phenotypic changes. Mutations to the virus hemagglutinin (HA) glycoprotein can modulate virus antigenicity and facilitate virus escape from natural or vaccine-induced immunity. The focus of this study was to identify evolutionary markers in the HA of H7N9 that drive escape from antibody-based immunity. To achieve this, we propagated low-pathogenicity H7N9 virus in the presence of polyclonal antiserum derived from ferrets infected with the same strain of virus (homologous antiserum). This selection process was repeated 10 times. The HA gene sequences of viruses recovered after the fifth passage showed that the viruses readily acquired mutations at three different amino acid positions (A125T, A151T, and L217Q). Further functional analysis of these mutations confirmed that the mutation at residue 217 in the HA was responsible for mediating changes to the immunological properties of the H7N9 virus.