Differences in cytokine production in human macrophages and in virulence in mice are attributable to the acidic polymerase protein of highly pathogenic influenza A virus subtype H5N1.
Differences in cytokine production in human macrophages and in virulence in mice are attributable to the acidic polymerase protein of highly pathogenic influenza A virus subtype H5N1.
复制标题
DOI：
10.1093/infdis/jis523
复制
发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Saori Sakabe;Ryo Takano;T. Nagamura-Inoue;N. Yamashita;C. A. Nidom;Mai thi Quynh Le;K. Iwatsuki-Horimoto-K.-Iwatsuki-H
中科院分区：
文献类型：
--
作者：
Saori Sakabe;Ryo Takano;T. Nagamura-Inoue;N. Yamashita;C. A. Nidom;Mai thi Quynh Le;K. Iwatsuki-Horimoto-K.-Iwatsuki-H
背景甲型流感病毒亚型H5 N1（以下称为“H5 N1”）感染人类的发病机制尚未完全了解，尽管高细胞因子血症被认为起作用。我们以前报道过，大多数H5 N1病毒诱导高细胞因子在人类巨噬细胞中的反应，而一些H5 N1病毒只诱导低水平的细胞因子的生产类似的季节性病毒诱导。方法为了鉴定H5 N1病毒在人巨噬细胞中细胞因子诱导的病毒分子决定簇，我们在高细胞因子诱导剂A/Vietnam/UT 3028 II/03 clone 2（VN 3028 IIcl 2）和低诱导剂A/Indonesia/UT 3006/05（IDN 3006）之间产生了一系列重组病毒，并评估了人巨噬细胞中细胞因子的表达。结果与IDN 3006相比，具有VN 3028 IIcl 2的酸性聚合酶（PA）基因的病毒在人巨噬细胞中表现出高水平的高细胞因子血症相关细胞因子表达，但在这些细胞中的病毒生长没有实质性差异。此外，VN 3028 IIcl 2的PA基因在小鼠中赋予增强的毒力。结论VN 3028 IIcl 2的PA基因影响人巨噬细胞的细胞因子产生和小鼠的毒力。这些发现提供了新的见解，在人类中的H5 N1感染的精氨酸介导的发病机制。
BACKGROUND The pathogenesis of influenza A virus subtype H5N1 (hereafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses. METHODS To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006) and evaluated cytokine expression in human macrophages. RESULTS Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice. CONCLUSIONS These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans.