Plasminogen-binding activity of neuraminidase determines the pathogenicity of influenza A virus
Plasminogen-binding activity of neuraminidase determines the pathogenicity of influenza A virus
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DOI：
10.1128/jvi.75.19.9297-9301.2001
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发表时间：
2001-10-01
影响因子：
5.4
通讯作者：
Kawaoka, Y
中科院分区：
文献类型：
--
作者：
Goto, H;Wells, K;Kawaoka, Y
当在体外表达时，A/WSN/33（WSN）病毒的神经氨酸酶（NA）结合并螯合细胞表面上的纤溶酶原，导致病毒血凝素的切割增强。为了获得NA的纤溶酶原结合活性增强WSN病毒的致病性的直接证据，我们产生了突变病毒，其NA缺乏纤溶酶原结合活性，因为在C末端的突变，从赖氨酸到精氨酸或亮氨酸。在胰蛋白酶的存在下，这些突变病毒复制类似于野生型病毒在细胞培养。相比之下，在纤溶酶原的存在下，突变病毒未能进行多个复制循环，而野生型病毒正常生长。突变病毒在小鼠体内的生长减弱，在大脑中完全不能生长。此外，另一种突变型WSN病毒在130位（N2编号为146）具有糖基化位点的NA，导致神经毒力丧失，在纤溶酶原存在的情况下无法在细胞培养物中生长。我们的结论是纤溶酶原结合活性的WSN NA决定其在小鼠中的致病性。
When expressed in vitro, the neuraminidase (NA) of A/WSN/33 (WSN) virus binds and sequesters plasminogen on the cell surface, leading to enhanced cleavage of the viral hemagglutinin. To obtain direct evidence that the plasminogen-binding activity of the NA enhances the pathogenicity of WSN virus, we generated mutant viruses whose NAs lacked plasminogen-binding activity because of a mutation at the C terminus, from Lys to Arg or Leu. In the presence of trypsin, these mutant viruses replicated similarly to wild-type virus in cell culture. By contrast, in the presence of plasminogen, the mutant viruses failed to undergo multiple cycles of replication while the wild-type virus grew normally. The mutant viruses showed attenuated growth in mice and failed to grow at all in the brain. Furthermore, another mutant WSN virus, possessing an NA with a glycosylation site at position 130 (146 in N2 numbering), leading to the loss of neurovirulence, failed to grow in cell culture in the presence of plasminogen. We conclude that the plasminogen-binding activity of the WSN NA determines its pathogenicity in mice.