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Characterization of two distinct neuraminidases from avian-origin human-infecting H7N9 influenza viruses

文献类型：期刊论文

作者Wu, Yan1,2; Bi, Yuhai1; Vavricka, Christopher J.1,3; Sun, Xiaoman1,2; Zhang, Yanfang4; Gao, Feng5,6; Zhao, Min1; Xiao, Haixia4; Qin, Chengfeng7; He, Jianhua8
刊名CELL RESEARCH
出版日期2013-12-01
卷号23期号:12页码:1347-1355
关键词H7N9 neuraminidase virus fitness sialidase activity drug resistance structural basis
英文摘要An epidemic of an avian-origin H7N9 influenza virus has recently emerged in China, infecting 134 patients of which 45 have died. This is the first time that an influenza virus harboring an N9 serotype neuraminidase (NA) has been known to infect humans. H7N9 viruses are divergent and at least two distinct NAs and hemagglutinins (HAs) have been found, respectively, from clinical isolates. The prototypes of these viruses are A/Anhui/1/2013 and A/Shanghai/1/2013. NAs from these two viruses are distinct as the A/Shanghai/1/2013 NA has an R294K substitution that can confer NA inhibitor oseltamivir resistance. Oseltamivir is by far the most commonly used anti-influenza drug due to its potency and high bioavailability. In this study, we show that an R294K substitution results in multidrug resistance with extreme oseltamivir resistance (over 100 000-fold) using protein-and virus-based assays. To determine the molecular basis for the inhibitor resistance, we solved high-resolution crystal structures of NAs from A/Anhui/1/2013 N9 (R294-containing) and A/Shanghai/1/2013 N9 (K294-containing). R294K substitution results in an unfavorable E276 conformation for oseltamivir binding, and consequently loss of inhibitor carboxylate interactions, which compromises the binding of all classical NA ligands/inhibitors. Moreover, we found that R294K substitution results in reduced NA catalytic efficiency along with lower viral fitness. This helps to explain why K294 has predominantly been found in clinical cases of H7N9 infection under the selective pressure of oseltamivir treatment and not in the dominant human-infecting viruses. This implies that oseltamivir can still be efficiently used in the treatment of H7N9 infections.
WOS标题词Science & Technology ; Life Sciences & Biomedicine
类目[WOS]Cell Biology
研究领域[WOS]Cell Biology
关键词[WOS]ACTIVE-SITE ; ANTIVIRAL RESISTANCE ; MAXIMUM-LIKELIHOOD ; H1N1 NEURAMINIDASE ; DRUG DESIGN ; IN-VITRO ; A VIRUS ; INHIBITORS ; SENSITIVITY ; MUTATIONS
收录类别SCI
语种英语
WOS记录号WOS:000328072600007
源URL[http://124.16.173.210/handle/834782/1226]  
专题天津工业生物技术研究所_蛋白质工程与疫苗实验室 高福_期刊论文
作者单位1.Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Beijing Inst Life Sci, Res Network Immun & Hlth RNIH, Beijing 100101, Peoples R China
4.Tianjin Inst Ind Biotechnol, Lab Prot Engn & Vaccines, Tianjin 300308, Peoples R China
5.Chinese Acad Sci, Inst Biophys, Lab Noncoding RNA, Beijing 100101, Peoples R China
6.Sichuan Univ, Sch Life Sci, Chengdu 610064, Sichuan, Peoples R China
7.Acad Mil Med Sci, Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai 201204, Peoples R China
9.Chinese Ctr Dis Control & Prevent China CDC, Off Director Gen, Beijing 102206, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Yan,Bi, Yuhai,Vavricka, Christopher J.,et al. Characterization of two distinct neuraminidases from avian-origin human-infecting H7N9 influenza viruses[J]. CELL RESEARCH,2013,23(12):1347-1355.
APA Wu, Yan.,Bi, Yuhai.,Vavricka, Christopher J..,Sun, Xiaoman.,Zhang, Yanfang.,...&Gao, George F..(2013).Characterization of two distinct neuraminidases from avian-origin human-infecting H7N9 influenza viruses.CELL RESEARCH,23(12),1347-1355.
MLA Wu, Yan,et al."Characterization of two distinct neuraminidases from avian-origin human-infecting H7N9 influenza viruses".CELL RESEARCH 23.12(2013):1347-1355.

入库方式： OAI收割

来源：天津工业生物技术研究所

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