Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses
Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses
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DOI：
10.4172/1747-0862.1000029
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发表时间：
2008-11
期刊：
影响因子：
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通讯作者：
H. Kido;Y. Okumura;E. Takahashi;Hai-yan Pan;Siye Wang;J. Chida;T. Le;M. Yano
中科院分区：
文献类型：
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作者：
H. Kido;Y. Okumura;E. Takahashi;Hai-yan Pan;Siye Wang;J. Chida;T. Le;M. Yano
甲型流感病毒（Influenza A virus，IAV）是人类最常见的传染性病原体之一，可引起相当高的发病率和死亡率。最近高致病性禽IAV H5 N1病毒的传播加强了防范大流行的重要性。在IAV感染的发病机制中，细胞蛋白酶在病毒进入细胞的过程中起关键作用，随后导致感染器官中的组织损伤。由于在IAV中不存在病毒膜融合糖蛋白血凝素前体（HA 0）的加工蛋白酶，因此病毒进入细胞主要由宿主细胞HA 0加工蛋白酶决定，所述HA 0加工蛋白酶通过蛋白水解激活膜融合活性。季节性人IAV的HA 0具有共有切割位点基序Q（E）-T/X-R，并且被迄今为止在使用小鼠适应的IAV或MDCK细胞中的基因表达系统的动物模型实验中鉴定的至少七种不同的胰蛋白酶型加工蛋白酶选择性加工。与高致病性禽流感（HPAI）A病毒的情况一样，HA 0的内切蛋白水解加工通过普遍存在的细胞加工蛋白酶发生，所述蛋白酶选择性地识别多碱基共有切割位点基序，如R-X-K/R-R和K-X-K/R-R。据报道，R-X-K/R-R基序的切割酶是trans-Golgi网络中的弗林蛋白酶和前蛋白转化酶（PC）5/6，而不是K-X-K/R-R基序。在这里，我们报告的新成员的II型跨膜丝氨酸蛋白酶的细胞膜，镶嵌丝氨酸蛋白酶大的形式（MSPL）和它的剪接变体TMPRSS 13，识别和切割两个R-X-K/R-R和K-X-K/R-R基序没有钙。此外，IAV感染显着上调潜伏异位胰腺胰蛋白酶，一种有效的HA加工蛋白酶，和前基质金属蛋白酶-9，在各种器官。这些蛋白酶可能协同损害脑中的血脑屏障和各种器官中血管的基底膜，导致严重水肿和多器官衰竭。本文综述了这些蛋白酶作为新的药物靶分子，通过抑制IAV增殖和预防多器官功能衰竭，而不是抗病毒药物、病毒神经氨酸酶抑制剂。
Influenza A virus (IAV) is one of the most common infectious pathogens in humans and causes considerable morbidity and mortality. The recent spread of highly-pathogenic avian IAV H5N1 viruses has reinforced the importance of pandemic preparedness. In the pathogenesis of IAV infection, cellular proteases play critical roles in the process of viral entry into cells that subsequently leads to tissue damage in the infected organs. Since there are no processing protease for the viral membrane fusion glycoprotein hemagglutinin precursor (HA0) in IAV, entry of the virus into cells is determined primarily by the host cellular HA0 processing proteases that proteolytically activate membrane fusion activity. HA0 of seasonal human IAV has the consensus cleavage site motif Q(E)-T/X-R and is selectively processed by at least seven different trypsin-type processing proteases identified to-date in animal model experiments using mouse-adapted IAV or gene expression system in MDCK cells. As is the case for the highly pathogenic avian influenza (HPAI) A virus, endoproteolytic processing of the HA0 occurs through ubiquitous cellular processing proteases, which selectively recognize the multi-basic consensus cleavage site motifs, such as R-X-K/R-R, and K-X-K/R-R. The cleavage enzymes for the R-X-K/R-R motif, but not K-X-K/R-R motif, have been reported to be furin and pro-protein convertase (PC)5/6 in the trans-Golgi network. Here we report new members of type II transmembrane serine proteases of the cell membrane, mosaic serine protease large form (MSPL) and its splice variant TMPRSS13, which recognize and cleave both R-X-K/R-R and K-X-K/R-R motifs without calcium. Furthermore, IAV infection significantly up-regulates a latent ectopic pancreatic trypsin, one of the potent HA processing proteases, and pro-matrix metalloprotease-9, in various organs. These proteases may synergistically damage the blood-brain barrier in the brain and basement membrane of blood vessels in various organs, resulting in severe edema and multiple organ failure. In this review, we discuss these proteases as new drug target molecules for IAV treatment acting by inhibition of IAV multiplication and prevention of multiple organ failure, other than anti-viral agents, viral neuraminidase inhibitors.