Mammalian Adaptive Mutations of the PA Protein of Highly Pathogenic Avian H5N1 Influenza Virus
Mammalian Adaptive Mutations of the PA Protein of Highly Pathogenic Avian H5N1 Influenza Virus
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DOI：
10.1128/jvi.03532-14
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发表时间：
2015-01
影响因子：
5.4
通讯作者：
Reina Yamaji;Shinya Yamada;M. Le;Mutsumi Ito;Yuko Sakai-Tagawa;Y. Kawaoka
中科院分区：
文献类型：
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作者：
Reina Yamaji;Shinya Yamada;M. Le;Mutsumi Ito;Yuko Sakai-Tagawa;Y. Kawaoka
高致病性H5 N1甲型流感病毒继续在禽类中传播，并引起零星的人类感染病例。因此，大流行病的威胁依然存在。然而，人类感染H5 N1病例主要限于与受感染家禽密切接触的个人。这些发现表明，H5 N1病毒需要获得适应性突变，以便在哺乳动物细胞中获得复制优势，从而突破物种屏障。据报道，聚合酶复合物的许多氨基酸突变可增强H5 N1病毒在哺乳动物细胞中的生长;然而，H5 N1病毒适应人类的机制仍不清楚。在此，我们提出，从越南人身上分离的H5 N1流感病毒（A/Vietnam/UT 36285/2010 [36285]）的PA增加了禽H5 N1病毒（A/chicken/Vietnam/TY 31/2005 [Ck/TY 31]）在人肺上皮A549细胞中生长的能力。5个PA氨基酸取代V44 I、V127 A、C241 Y、A343 T和I573 V，这在来自人类和禽类的H5 N1病毒中是罕见的，增强了该病毒在A549细胞中的生长能力。此外，这些突变增加了病毒在小鼠中的致病性，表明它们有助于适应哺乳动物宿主。有趣的是，PA-241 Y（36285编码）在90%以上的人类季节性H1N1病毒中是保守的，这表明PA-241 Y有助于病毒适应人类肺细胞和哺乳动物宿主。重要性高致病性H5 N1禽流感病毒中的许多氨基酸替换已被证明有助于适应哺乳动物宿主。然而，没有自然分离的H5 N1病毒引起广泛的人际传播，这表明需要额外的，尚未确定的氨基酸突变才能适应人类。在这里，我们报告了PA中的五个氨基酸取代（V44 I，V127 A，C241 Y，A343 T和I573 V）有助于H5 N1病毒在人肺细胞中的复制效率和小鼠中的高毒力。这些结果有助于评估分离株的大流行风险，并进一步了解H5 N1病毒适应哺乳动物宿主的机制。
ABSTRACT Highly pathogenic H5N1 influenza A viruses continue to circulate among avian species and cause sporadic cases of human infection. Therefore, the threat of a pandemic persists. However, the human cases of H5N1 infection have been limited mainly to individuals in close contact with infected poultry. These findings suggest that the H5N1 viruses need to acquire adaptive mutations to gain a replicative advantage in mammalian cells to break through the species barrier. Many amino acid mutations of the polymerase complex have been reported to enhance H5N1 virus growth in mammalian cells; however, the mechanism for H5N1 virus of adaptation to humans remains unclear. Here, we propose that the PA of an H5N1 influenza virus isolated from a human in Vietnam (A/Vietnam/UT36285/2010 [36285]) increased the ability of an avian H5N1 virus (A/chicken/Vietnam/TY31/2005 [Ck/TY31]) to grow in human lung epithelial A549 cells. The five PA amino acid substitutions V44I, V127A, C241Y, A343T, and I573V, which are rare in H5N1 viruses from human and avian sources, enhanced the growth capability of this virus in A549 cells. Moreover, these mutations increased the pathogenicity of the virus in mice, suggesting that they contribute to adaptation to mammalian hosts. Intriguingly, PA-241Y, which 36285 encodes, is conserved in more than 90% of human seasonal H1N1 viruses, suggesting that PA-241Y contributes to virus adaptation to human lung cells and mammalian hosts. IMPORTANCE Many amino acid substitutions in highly pathogenic H5N1 avian influenza viruses have been shown to contribute to adaptation to mammalian hosts. However, no naturally isolated H5N1 virus has caused extensive human-to-human transmission, suggesting that additional, as-yet unidentified amino acid mutations are needed for adaptation to humans. Here, we report that five amino acid substitutions in PA (V44I, V127A, C241Y, A343T, and I573V) contribute to the replicative efficiency of H5N1 viruses in human lung cells and to high virulence in mice. These results are helpful for assessing the pandemic risk of isolates and further our understanding of the mechanism of H5N1 virus adaptation to mammalian hosts.