Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice.
Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice.
复制标题
小鼠上呼吸道中H5N1流感A病毒的生长。
DOI：
10.1371/journal.ppat.0030133
复制
发表时间：
2007-10-05
期刊：
影响因子：
6.7
通讯作者：
Kawaoka, Yoshihiro
中科院分区：
文献类型：
--
作者：
Hatta, Masato;Hatta, Yasuko;Kim, Jin Hyun;Watanabe, Shinji;Shinya, Kyoko;Nguyen, Tung;Lien, Phuong Song;Le, Quynh Mai;Kawaoka, Yoshihiro
高致病性禽流感H5N1甲型流感病毒已经在亚洲、欧洲和非洲蔓延，引起了全世界对其大流行可能性的严重关注。尽管已有250多人感染了这些病毒，因此死亡率很高，但导致H5N1病毒在人类之间有效传播的分子机制仍然不清楚。我们使用小鼠模型来研究PB2病毒蛋白627位的氨基酸在哺乳动物呼吸道有效复制H5N1病毒中的作用。在PB2的627位具有Lys的病毒，即使在33℃的低温下，也能在肺和鼻甲以及细胞中有效复制。在该位置具有Glu的病毒在鼻甲中的复制不如在肺中好，在较低温度下在细胞中的复制也较差。这些结果表明，PB2-627的Lys赋予禽流感H5N1病毒在哺乳动物的上呼吸道和下呼吸道高效生长的优势。因此，在包括人类(含唾液酸α-2，6-半乳糖)受体的其他病毒特性变化的背景下，上呼吸道的有效病毒生长可能为禽流感病毒适应人类和有效的人与人之间的病毒传播提供平台。自2003年以来，高致病性禽流感H5N1甲型流感病毒在世界各地传播，引起了全世界对其大流行可能性的严重关切。尽管尚未发生这种病毒在人与人之间的有效传播，但这些病毒获得这种能力的潜力是显而易见的。血凝素(HA)蛋白的受体特异性被认为是影响H5N1病毒有效传播的主要因素。然而，一些从人类身上分离出来的具有人类受体特异性的H5N1病毒仍然无法在人类之间有效传播。因此，除了受体结合的HA蛋白外，病毒蛋白中的氨基酸替换对于H5N1禽流感病毒的有效生长和人与人之间的传播必须是必要的。在我们的研究中，我们定义了PB2 627位氨基酸对H5N1流感病毒在小鼠上呼吸道高效复制的贡献作为哺乳动物模型。由于人类上呼吸道的有效病毒生长可以通过咳嗽和打喷嚏促进病毒排泄，因此有助于哺乳动物这一部位高效生长的PB2氨基酸627的突变可能是有效的人传人的先决条件。
Highly pathogenic avian H5N1 influenza A viruses have spread throughout Asia, Europe, and Africa, raising serious worldwide concern about their pandemic potential. Although more than 250 people have been infected with these viruses, with a consequent high rate of mortality, the molecular mechanisms responsible for the efficient transmission of H5N1 viruses among humans remain elusive. We used a mouse model to examine the role of the amino acid at position 627 of the PB2 viral protein in efficient replication of H5N1 viruses in the mammalian respiratory tract. Viruses possessing Lys at position 627 of PB2 replicated efficiently in lungs and nasal turbinates, as well as in cells, even at the lower temperature of 33 °C. Those viruses possessing Glu at this position replicated less well in nasal turbinates than in lungs, and less well in cells at the lower temperature. These results suggest that Lys at PB2–627 confers to avian H5N1 viruses the advantage of efficient growth in the upper and lower respiratory tracts of mammals. Therefore, efficient viral growth in the upper respiratory tract may provide a platform for the adaptation of avian H5N1 influenza viruses to humans and for efficient person-to-person virus transmission, in the context of changes in other viral properties including specificity for human (sialic acid α-2,6-galactose containing) receptors. Highly pathogenic avian H5N1 influenza A viruses have spread around the world since 2003, raising serious worldwide concern about their pandemic potential. Although efficient human-to-human transmission of this virus has not yet occurred, the potential of these viruses to acquire the ability is evident. The receptor specificity of the haemmaglutinin (HA) protein is considered a main factor affecting efficient transmission of H5N1 viruses. Yet, some H5N1 viruses isolated from humans that possess human receptor specificity have still failed to spread efficiently among humans. Therefore, amino acid substitutions in viral proteins other than the receptor-binding HA protein must be necessary for efficient growth and person-to-person transmission of avian H5N1 influenza virus. In our study, we defined the contribution of the amino acid at position 627 of the PB2 to efficient replication of H5N1 influenza viruses in the upper respiratory tracts of mice as a mammalian model. Because efficient viral growth in the upper respiratory tract of humans can facilitate virus excretion by coughing and sneezing, a mutation of PB2 amino acid 627, which contributes to efficient growth at this site in a mammal, may be prerequisite for efficient human-to-human transmission.