Acquisition of human-type receptor binding specificity by new H5N1 influenza virus sublineages during their emergence in birds in Egypt.
Acquisition of human-type receptor binding specificity by new H5N1 influenza virus sublineages during their emergence in birds in Egypt.
复制标题
新的H5N1流感病毒在埃及鸟类出现期间，通过新的H5N1流感病毒sublineage的特异性获得了人类型受体结合的特异性。
DOI：
10.1371/journal.ppat.1002068
复制
发表时间：
2011-05
期刊：
影响因子：
6.7
通讯作者：
Ikuta K
中科院分区：
文献类型：
--
作者：
Watanabe Y;Ibrahim MS;Ellakany HF;Kawashita N;Mizuike R;Hiramatsu H;Sriwilaijaroen N;Takagi T;Suzuki Y;Ikuta K
H5 N1亚型高致病性禽流感病毒目前在亚洲、欧洲和非洲广泛传播，人类死亡率为60%。特别是，自2009年以来，埃及意外地出现了H5 N1病毒感染人间病例的最高数量，占全球病例的50%以上，但这种高发病率的基础尚未阐明。病毒血凝素（HA）的受体结合亲和力从α 2，3-连接的唾液酸（SA）变为α 2，6-连接的SA被认为是H5 N1病毒成为大流行所必需的。在这项研究中，我们对2006年至2009年在埃及分离的H5 N1病毒进行了系统发育分析。系统发育结果表明，最近的人类分离物聚集成几个新的H5亚系，表明他们的HA已经改变了他们的受体特异性。使用反向遗传学，我们发现这些H5亚系获得了对α 2，6 SA的增强的结合亲和力以及对α 2，3 SA的残余亲和力，并鉴定了产生这种新受体特异性的氨基酸突变。在HA残基192处具有单突变或在HA残基129和151处具有双突变的重组H5 N1病毒在人下呼吸道中具有增加的附着和感染性，但在喉中没有。这些发现与突变病毒在小鼠中的毒力增强有关。有趣的是，这些H5病毒对α 2，6 SA的亲和力增加，在鸟类种群的病毒多样化过程中出现，随后传播给人类。我们的研究结果表明，具有α 2，6 SA特异性的新H5亚系的出现导致埃及人H5 N1流感病毒感染的随后增加，并为了解该病毒的大流行潜力提供了数据。尽管高致病性H5 N1禽流感病毒缺乏有效的人际传播机制，但这些病毒在中国、印度尼西亚、越南和埃及的鸟类中流行。在人类病例占H5 N1流感病例总数80%以上的地区，指出了禽-人传播的热点。宿主之间的循环可能使H5 N1病毒获得氨基酸变化，从而使禽-人传播和最终人-人传播成为可能。病毒血凝素（HA）的受体特异性被认为是影响病毒有效传播的主要因素。H5病毒HA中的几个氨基酸取代增加了它们的人型受体特异性，已经在来自患者的病毒分离物中描述过，但它们的流行程度有限。相比之下，我们在这里表明，新的H5亚系在埃及已经获得了受体特异性的变化，在其多样化的鸟类。我们发现这些亚系中的病毒在人类下呼吸道中表现出更强的附着性和感染性，但在喉部中则不然。我们的研究结果可能无法就H5 N1病毒在埃及的高流行潜力得出结论，但有助于解释为什么埃及最近的人类H5病例数是世界上最高的。
Highly pathogenic avian influenza A virus subtype H5N1 is currently widespread in Asia, Europe, and Africa, with 60% mortality in humans. In particular, since 2009 Egypt has unexpectedly had the highest number of human cases of H5N1 virus infection, with more than 50% of the cases worldwide, but the basis for this high incidence has not been elucidated. A change in receptor binding affinity of the viral hemagglutinin (HA) from α2,3- to α2,6-linked sialic acid (SA) is thought to be necessary for H5N1 virus to become pandemic. In this study, we conducted a phylogenetic analysis of H5N1 viruses isolated between 2006 and 2009 in Egypt. The phylogenetic results showed that recent human isolates clustered disproportionally into several new H5 sublineages suggesting that their HAs have changed their receptor specificity. Using reverse genetics, we found that these H5 sublineages have acquired an enhanced binding affinity for α2,6 SA in combination with residual affinity for α2,3 SA, and identified the amino acid mutations that produced this new receptor specificity. Recombinant H5N1 viruses with a single mutation at HA residue 192 or a double mutation at HA residues 129 and 151 had increased attachment to and infectivity in the human lower respiratory tract but not in the larynx. These findings correlated with enhanced virulence of the mutant viruses in mice. Interestingly, these H5 viruses, with increased affinity to α2,6 SA, emerged during viral diversification in bird populations and subsequently spread to humans. Our findings suggested that emergence of new H5 sublineages with α2,6 SA specificity caused a subsequent increase in human H5N1 influenza virus infections in Egypt, and provided data for understanding the virus's pandemic potential. Even though highly pathogenic avian H5N1 influenza viruses lack an efficient mechanism for human-human transmission, these viruses are endemic in birds in China, Indonesia, Viet Nam and Egypt. Hotspots for bird-human transmission are indicated in areas where human cases are more than 80% of total H5N1 influenza cases. Circulation among hosts may allow H5N1 virus to acquire amino acid changes enabling efficient bird-human transmission and eventually human-human transmission. The receptor specificity of viral hemagglutinin (HA) is considered a main factor affecting efficient transmissibility. Several amino acid substitutions in H5 virus HAs that increase their human-type receptor specificity have been described in virus isolates from patients, but their prevalence has been limited. In contrast, we show here that new H5 sublineages in Egypt have acquired a change in receptor specificity during their diversification in birds. We found that viruses in those sublineages exhibited increased attachment and infectivity in the human lower respiratory tract, but not in the larynx. Our findings may not allow a conclusion on the high pandemic potential of H5N1 virus in Egypt, but helps explain why Egypt has recently had the highest number of human H5 cases worldwide.
登录
查看更多内容
影响因子：
5.4
作者：
Fusaro, Alice;Nelson, Martha I.;Cattoli, Giovanni
通讯作者：
Cattoli, Giovanni
影响因子：
4.3
作者：
Guo, Chao-Tan;Takahashi, Noriko;Suzuki, Yasuo
通讯作者：
Suzuki, Yasuo
影响因子：
3.7
作者：
Ayora-Talavera G;Shelton H;Scull MA;Ren J;Jones IM;Pickles RJ;Barclay WS
通讯作者：
Barclay WS
影响因子：
5.4
作者：
Chen, HL;Li, YB;Kawaoka, Y
通讯作者：
Kawaoka, Y
影响因子：
5.4
作者：
Chutinimitkul, Salin;van Riel, Debby;de Wit, Emmie
通讯作者：
de Wit, Emmie