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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Changes In H5n1 Influenza Virus Hemagglutinin Receptor Binding Domain Affect Systemic Spread
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Changes In H5n1 Influenza Virus Hemagglutinin Receptor Binding Domain Affect Systemic Spread

机译：H5n1流感病毒血凝素受体结合域的变化影响系统传播

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摘要

The HA of influenza virus is a receptor-binding and fusion protein that isrnrequired to initiate infection. The HA receptor-binding domain determines the species of sialyl receptors recognized by influenza viruses. Here, we demonstrate that changes in the HA receptor-binding domain alter the ability of the H5N1 virus to spread system ically in mice. The A/Vietnam/1203/04 (VN1203) and A/Hong Kong/ 213/03 (HK213) viruses are consistently lethal to domestic chickens but differ in their pathogenicity to mammals. Insertion of the VN1203 HA and neuraminidase (NA) genes into recombinant HK213 virus expanded its tissue tropism and increased its lethality in mice; conversely, insertion of HK213 HA and NA genes into recombinant VN1203 virus decreased its systemic spread and lethality. The VN1203 and HK213 HAs differ by 10 aa, and HK213 HA has shown greater binding affinity for synthetic α2,6-linked sialyl receptor. Introduction of an S227N change and removal of W-linked glycosylation at residue 158 increased the α2,6-binding affinity of VN1203 HA. Recombinant VN1203 virus carrying the S227N change alone or with the residue-158 glycosylation site removed showed reduced lethality and systemic spread in mice but not in domestic chickens. Wild-type VN1203 virus exhibited the greatest efficiency in systemic spread after intramuscular inoculation and in infection of mouse bone marrow-derived dendritic cells and conventional pulmonary dendritic cells. These results show that VN1203 HA glycoprotein confers pathogenicity by facilitating systemic spread in mice; they also suggest that a minor change in receptor binding domain may modulate the virulence of H5N1 viruses.
机译：流感病毒的HA是一种受体结合和融合蛋白，需要启动感染。 HA受体结合域决定了流感病毒识别的唾液酸受体的种类。在这里，我们证明了HA受体结合域的变化改变了H5N1病毒在小鼠体内系统传播的能力。 A / Vietnam / 1203/04（VN1203）和A / Hong Kong / 213/03（HK213）病毒对家禽始终具有致命性，但对哺乳动物的致病性却有所不同。将VN1203 HA和神经氨酸酶（NA）基因插入重组HK213病毒可扩大其组织嗜性，并增加其对小鼠的致死率。相反，将HK213 HA和NA基因插入重组VN1203病毒可降低其系统扩散和致死性。 VN1203和HK213 HA之间相差10个氨基酸，HK213 HA对合成的α2,6-连接的唾液酸受体显示出更大的结合亲和力。引入S227N改变并去除残基158的W联糖基化可增加VN1203 HA的α2,6-结合亲和力。单独携带S227N改变或去除残基158糖基化位点的重组VN1203病毒在小鼠中可显示出降低的致死性和全身性传播，但在家禽中却不可见。野生型VN1203病毒在肌肉注射后全身扩散以及感染小鼠骨髓来源的树突状细胞和常规肺树突状细胞方面表现出最大的效率。这些结果表明，VN1203 HA糖蛋白通过促进小鼠的全身扩散而赋予了致病性。他们还表明，受体结合结构域的微小变化可能会调节H5N1病毒的毒力。

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