The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases
The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases
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DOI：
10.1128/jvi.02693-15
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发表时间：
2016-05-01
影响因子：
5.4
通讯作者：
Schughart, Klaus
中科院分区：
文献类型：
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作者：
Kuehn, Nora;Bergmann, Silke;Schughart, Klaus
流感病毒血凝素(HA)被宿主细胞蛋白酶切割是病毒活化和感染性所必需的。在人类和小鼠中，II型跨膜蛋白水解酶家族(TTSP)的成员，如TMPRSS2、TMPRSS4和TMPRSS11d(HAT)，已被证明在体外切割流感病毒HA以激活病毒并具有感染性。最近，我们报道了在基因敲除的小鼠中，单个HA激活的蛋白水解酶基因TMPRSS2的失活可以抑制H1N1流感病毒的传播。然而，在TMPRSS2基因敲除小鼠感染H3N2型流感病毒后，仅观察到存活率略有增加，小鼠体重仍然下降。在这项研究中，我们研究了另一种类胰蛋白酶TMPRSS4。TMPRSS2和TMPRSS4在小鼠肺中表达于相同的细胞类型。仅在基因敲除小鼠中删除Tmprss 4并不能保护它们在感染H3N2流感病毒时体重减轻和死亡。相比之下，TMPRSS2(-/-)Tmprss4(-/-)双基因敲除小鼠除了体重减轻和死亡率降低外，病毒传播和肺部病理都显著减少。因此，我们的结果确定TMPRSS4是除TMPRSS2外的第二种宿主细胞蛋白酶，能够在体内激活H3N2型流感病毒的血凝素。
Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g., TMPRSS2, TMPRSS4, and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro. Recently, we reported that inactivation of a single HA-activating protease gene, Tmprss2, in knockout mice inhibits the spread of H1N1 influenza viruses. However, after infection of Tmprss2 knockout mice with an H3N2 influenza virus, only a slight increase in survival was observed, and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knockout mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast, Tmprss2(-/-) Tmprss4(-/-) double-knockout mice showed a remarkably reduced virus spread and lung pathology, in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo.