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Discovery of the potentiating proteases for influenza virus infection and their inhibitors as defensive compounds

发现流感病毒感染的增强蛋白酶及其作为防御化合物的抑制剂

基本信息

批准号：
10557033
负责人：
KIDO Hiroshi
金额：
$ 8.26万
依托单位：
Institute for Enzyme Research, The University of Tokusahima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Post-translational proteolytic cleavage of precursors of the envelope fusion glycoproteins of RNA viruses is indispensable for virus entry into host cells. It is widely known that the pathogenicity of mammalian and nonpathogenic avian influenza viruses, and Sendai virus is primarily determined by host cellular processing proteases in the respiratory tract, which proteolytically induce fusion of viral envelope glycoproteins, HA of influenza viruses, and F0 of Sendai virus with the plasma membrane of target cells, allowing the viral genome to enter the cytoplasm. In the period granted by this foundation, we found new members of protease in airway that, like tryptase Clara, can process influenza A virus hemagglutinin and Sendai virus envelope fusion glycoprotein. One was found in the epithelial cells of the upward divisions of bronchioles and identified to be a mini-plasmin. Mini-plasmin potentiated the replication of broad-spectrum influenza A viruses and Sendai virus, even that of the plasmin-insensitive influenza A virus strain. The other was found in the epithelial cells of alveolar of rat lungs and was identified to be an ectopic anionic pancreatic trypsin. Mucus protease inhibitor(MPI)in nasal liquids and bronchial lavage inhibited the activity of tryptase Clara and partly that of trypsin. Mini-plasmin was not inhibited by α1-antiplasmin and MPI.These findings indicate that there are several proteases potentiating the infectivity of influenza virus in different loci in airway and the infectivity of influenza virus is regulated by the balance between the amounts of these proteases and their inhibitors in airway.

RNA病毒包膜融合糖蛋白前体的翻译后蛋白水解切割是病毒进入宿主细胞所必需的。众所周知，哺乳动物和非致病性禽流感病毒以及仙台病毒的致病性主要由呼吸道中的宿主细胞加工蛋白酶决定，所述蛋白酶通过蛋白水解诱导病毒包膜糖蛋白、流感病毒的HA和仙台病毒的F0与靶细胞的质膜融合，从而允许病毒基因组进入细胞质。在该基金会的资助下，我们在气道中发现了新的蛋白酶成员，它们与类胰蛋白酶Clara一样，可以处理甲型流感病毒血凝素和仙台病毒包膜融合糖蛋白。一种在细支气管向上分支的上皮细胞中发现，并被鉴定为微型纤溶酶。微型纤溶酶可增强广谱甲型流感病毒和仙台病毒的复制，甚至增强对纤溶酶不敏感的甲型流感病毒株的复制。另一种存在于大鼠肺泡上皮细胞中，经鉴定为异位阴离子胰蛋白酶。鼻液和支气管灌洗液中的粘液蛋白酶抑制剂（MPI）抑制类胰蛋白酶Clara的活性，部分抑制胰蛋白酶的活性。α1-抗纤溶酶和MPI均不抑制微小纤溶酶，提示在气道不同部位存在多种增强流感病毒感染性的蛋白酶，流感病毒的感染性受这些蛋白酶及其抑制剂在气道中的平衡调节。