The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity and Transmissibility in Ducks
The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity and Transmissibility in Ducks
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DOI：
10.1128/jvi.02069-09
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发表时间：
2010-02-01
影响因子：
5.4
通讯作者：
Russell, Charles J.
中科院分区：
文献类型：
--
作者：
Reed, Mark L.;Bridges, Olga A.;Russell, Charles J.
虽然流感病毒血凝素（HA）蛋白的膜融合的分子机制已在体外被广泛研究，但酸依赖性HA蛋白活化在病毒复制、发病机制和体内传播中的作用尚未被表征。为了研究HA蛋白活化的pH的生物学意义，我们比较了具有改变的HA蛋白酸稳定性的四种重组病毒与野生型流感病毒A/鸡/越南/C58/04（H5 N1）在体外和野鸭中的性质。在pH 5.9下激活野生型病毒的膜融合。野生型病毒的计算环境持久性为62天，并造成广泛的发病率，死亡率，脱落，并在野鸭传播。N114 K突变使HA活化的pH值增加0.5个单位，导致复制、遗传稳定性和环境稳定性降低。通过Y23 H和K58 I突变激活的pH值的+0.4和-0.5单位的变化分别减少了绿头鸭的体重减轻、死亡率、脱落和传播。H24 Q突变使活化pH值降低0.3单位，导致体重减轻、死亡、临床症状和脱落，与野生型相似。然而，HA-H24（1）Q病毒更广泛地进入饮用水，并在环境中持续更长时间。H5 HA蛋白活化的pH在H5 N1流感病毒在鸭体内的繁殖中起着关键作用，可能是流感病毒生态学中的一个新的分子因子。数据还表明，H5 N1神经氨酸酶活性在体外增加HA蛋白活化的pH。
While the molecular mechanism of membrane fusion by the influenza virus hemagglutinin (HA) protein has been studied extensively in vitro, the role of acid-dependent HA protein activation in virus replication, pathogenesis, and transmission in vivo has not been characterized. To investigate the biological significance of the pH of activation of the HA protein, we compared the properties of four recombinant viruses with altered HA protein acid stability to those of wild-type influenza virus A/chicken/Vietnam/C58/04 (H5N1) in vitro and in mallards. Membrane fusion by wild-type virus was activated at pH 5.9. Wild-type virus had a calculated environmental persistence of 62 days and caused extensive morbidity, mortality, shedding, and transmission in mallards. An N114K mutation that increased the pH of HA activation by 0.5 unit resulted in decreased replication, genetic stability, and environmental stability. Changes of +0.4 and -0.5 unit in the pH of activation by Y23H and K58I mutations, respectively, reduced weight loss, mortality, shedding, and transmission in mallards. An H24Q mutation that decreased the pH of activation by 0.3 unit resulted in weight loss, mortality, clinical symptoms, and shedding similar to those of the wild type. However, the HA-H24(1)Q virus was shed more extensively into drinking water and persisted longer in the environment. The pH of activation of the H5 HA protein plays a key role in the propagation of H5N1 influenza viruses in ducks and may be a novel molecular factor in the ecology of influenza viruses. The data also demonstrate that H5N1 neuraminidase activity increases the pH of activation of the HA protein in vitro.