导读：
自2013年H7N9流感病毒出现以来，其已经造成了5波人感染疫情。截止目前已报道1567例H7N9感染病例，并造成615人死亡，感染致死率达39.2%。世界科学家争先寻求造成这种现象的原因。2018年3月21日，中国科学院流感研究与预警中心（CASCIRE）在线发表在国际病毒学杂志Journal of Virology上题为“New Threats from H7N9 Influenza Virus: Spread and Evolution of High- and Low-Pathogenicity Variants with High Genomic Diversity in Wave Five”（http://jvi.asm.org/content/early/2018/03/15/JVI.00301-18.long) 的研究论文，从病毒流行分布、流行模式和病毒遗传变异层面给出了答案。
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Figure 1 The temporal distributions of H7N9 human infections during Wave Five.
CASCIRE自2013年H7N9出现，对其病毒溯源（Lancet，2013）、致病和跨种间传播分子机制（Science, 2013; Journal of Virology, 2015、2016）、耐药分子机制（Cell Research，2013）、基于耐药机制的抗流感新药开发（Journal of Medicinal Chemistry，2016）等一系列研究成果，而本研究为深入了解H7N9流感病毒流行传播和致病机制以及科学防控H7N9提供了理论依据。
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Figure 2 The surveillance network of CASCIRE.
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Figure 3 The spatial distributions of H7N9 human infections during Wave Five.
病毒的遗传多样性：
1) 深入研究发现HP-H7N9起源于G1基因型LP-H7N9，其在HA裂解位点处发生插入性突变（插入了“KRTA”氨基酸基序）形成了含有多个碱性氨基酸裂解位点的HP-H7N9，在此基础上进化形成了4种HP-H7N9 HA裂解位点基序，即PKGKRTAR/G、PKGKRIAR/G、PKRKRAAR/G和PKRKRTAR/G。有意思的是，近一半HP-H7N9病毒属于G3基因型。2)值得注意的是，除人源H7N9病毒外，几乎所有非人源H7N9病毒分离株都含有哺乳动物适应性突变（PB2基因K526R、A588V或E627K突变），并且个别禽源H7N9病毒株还发现有神经氨酸酶抑制类药物（NAIs）耐药性突变（NA基因R292K突变）。
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Figure 4 Distinctive amino acid variations in HA and NA of HP-H7N9 compared to LP-H7N9.
2）H7N9亚型低致病力禽流感病毒（LP-H7N9）和高致病力禽流感病毒（HP-H7N9）全基因组均表现出动态重配，编码病毒囊膜蛋白HA和NA的基因，在不同谱系（长江系和珠江系）间重配。
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Figure 5 Phylogenies of HA and NA genes of H7N9 viruses from different waves.
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Figure 6 Schematic representation of evolutionary pathway of the H7N9 viruses during Wave Five.
ABSTRACT
H7N9 virus has caused five infection waves since it emerged in 2013. The highest number of human cases was seen in Wave Five; however, the underlying reasons have not been thoroughly elucidated. In this study, the geographical distribution, phylogeny and genetic evolution of 240 H7N9 viruses in Wave Five, including 35 new isolates from patients and poultry in nine provinces, were comprehensively analyzed together with strains from first four waves. Geographical distribution analysis displayed the newly-emerging highly pathogenic (HP) and low pathogenic (LP) H7N9 viruses were co-circulating, causing human and poultry infections across China. Genetic analysis indicated that dynamic reassortment of the internal genes among LP-H7N9/H9N2/H6Ny and HP-H7N9, as well as the surface genes between Yangtze and Pearl River Delta lineages resulted in at least 36 genotypes, with three major genotypes (G1, A/chicken/Jiangsu/SC537/2013-like, G3, A/Chicken/Zhongshan/ZS/2017-like and G11, A/Anhui/40094/2015-like). The HP-H7N9 likely evolved from G1 LP-H7N9 by the insertion of a “KRTA” motif at the cleavage site (CS), then evolved into fifteen genotypes with four different CS motifs including PKGKRTAR/G, PKGKRIAR/G, PKRKRAAR/G and PKRKRTAR/G. Approximately 46% (28/61) of HP strains belonged to G3. Importantly, neuraminidase (NA) inhibitor resistance (R292K in NA) and mammalian adaptation (eg. E627K and A588V in PB2) mutations were found in a few non-human-derived HP-H7N9 strains. In summary, the enhanced prevalence and diverse genetic characteristics with mammalian-adapted and NAI-resistant mutations may have contributed towards increased numbers of human infections in Wave Five.
参考文献
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