The HA and NS genes of human H5N1 influenza A virus contribute to high virulence in ferrets.
The HA and NS genes of human H5N1 influenza A virus contribute to high virulence in ferrets.
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DOI：
10.1371/journal.ppat.1001106
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发表时间：
2010-09-16
期刊：
影响因子：
6.7
通讯作者：
Kawaoka Y
中科院分区：
文献类型：
--
作者：
Imai H;Shinya K;Takano R;Kiso M;Muramoto Y;Sakabe S;Murakami S;Ito M;Yamada S;Le MT;Nidom CA;Sakai-Tagawa Y;Takahashi K;Omori Y;Noda T;Shimojima M;Kakugawa S;Goto H;Iwatsuki-Horimoto K;Horimoto T;Kawaoka Y
高致病性H5N1甲型流感病毒已经蔓延到亚洲、欧洲和非洲。已经报告了500多例人类感染H5N1病毒，致死率很高。为了了解H5N1病毒在哺乳动物中高毒力的分子基础，我们对几种从人类分离的H5N1病毒在雪貂身上的毒力进行了测试，发现A/越南/UT3062/04(UT3062)毒力最强，A/越南/UT3028/03(UT3028)毒力最强。然后，我们在这两种病毒之间产生了一系列重新配对的病毒，并评估了它们在雪貂身上的毒力。所有同时具有UT3062血凝素(HA)和非结构蛋白(NS)基因的病毒都是高毒力的。相比之下，所有拥有UT3028 HA或NS基因的人在雪貂中都是弱化的。这些结果表明，HA和NS基因是导致这两种病毒对雪貂毒力差异的原因。氨基酸差异在HA的134位，NS1的200位和205位，NS2的47位和51位。我们发现，通过从红细胞中洗脱病毒来衡量，HA第134位的残基改变了病毒的受体结合特性。此外，NS1第200位和205位的残基都有助于增强I型干扰素(IFN)的拮抗活性。这些发现进一步加深了我们对H5N1病毒在哺乳动物中致病性决定因素的理解。高致病性H5N1甲型流感病毒已在15个国家造成500多人感染，致死率约为60%，并继续构成大流行威胁。最近甲型H1N1流感大流行病毒在全球范围内的传播引发了人们对H5N1病毒与其他流感病毒之间重新分类的担忧。然而，H5N1病毒在哺乳动物中高毒力的分子决定因素还不完全清楚。因此，我们在雪貂模型中研究了它们的毒力，这是一种被广泛接受的评估人类流感病毒复制的动物模型。我们鉴定了血凝素中的一个氨基酸和非结构蛋白中的四个氨基酸，它们与人H5N1病毒A/越南/UT3062/04的高毒力有关。我们还发现，血凝素中的氨基酸改变了它的受体结合特性，非结构蛋白1中的氨基酸影响了它的干扰素拮抗能力。这些发现为H5N1病毒在哺乳动物中的发病机制提供了洞察力。
Highly pathogenic H5N1 influenza A viruses have spread across Asia, Europe, and Africa. More than 500 cases of H5N1 virus infection in humans, with a high lethality rate, have been reported. To understand the molecular basis for the high virulence of H5N1 viruses in mammals, we tested the virulence in ferrets of several H5N1 viruses isolated from humans and found A/Vietnam/UT3062/04 (UT3062) to be the most virulent and A/Vietnam/UT3028/03 (UT3028) to be avirulent in this animal model. We then generated a series of reassortant viruses between the two viruses and assessed their virulence in ferrets. All of the viruses that possessed both the UT3062 hemagglutinin (HA) and nonstructural protein (NS) genes were highly virulent. By contrast, all those possessing the UT3028 HA or NS genes were attenuated in ferrets. These results demonstrate that the HA and NS genes are responsible for the difference in virulence in ferrets between the two viruses. Amino acid differences were identified at position 134 of HA, at positions 200 and 205 of NS1, and at positions 47 and 51 of NS2. We found that the residue at position 134 of HA alters the receptor-binding property of the virus, as measured by viral elution from erythrocytes. Further, both of the residues at positions 200 and 205 of NS1 contributed to enhanced type I interferon (IFN) antagonistic activity. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals. Highly pathogenic H5N1 influenza A viruses have caused more than 500 human infections with approximately 60% lethality in 15 countries and continue to pose a pandemic threat. The recent worldwide spread of pandemic H1N1 influenza A viruses raises the concern of reassortment between the H5N1 viruses and other influenza viruses. However, the molecular determinants for high virulence of the H5N1 viruses in mammals are not fully understood. We, therefore, investigated their virulence in a ferret model, which is a widely accepted animal model for assessing human influenza virus replication. We identified an amino acid in hemagglutinin and four amino acids in nonstructural proteins that are associated with high virulence of a human H5N1 virus, A/Vietnam/UT3062/04. We also found that the amino acid in hemagglutinin changes its receptor-binding property and the amino acids in nonstructural protein 1 affect its interferon antagonistic ability. These findings provide insight into the pathogenesis of H5N1 viruses in mammals.
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影响因子：
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