·推荐论文摘要·

·推荐论文摘要·

具有常数输入的H7N9禽流感动力学模型分析

郭树敏，李学志

研究了新型的禽流感病毒传播的禽类-人类动力学模型。在有染病禽类输入和无染病禽类输入两种情况下，得到了系统的平衡点的存在性与基本再生数，并给出了系统的无病平衡点和地方病平衡点的稳定性条件。

H7N9禽流感；动力学模型；基本再生数；稳定性

来源出版物：信阳师范学院学报（自然科学版）, 2017, 30(1): 13-16

联系邮箱：郭树敏，shuminguo123456@ 126.com

人用H7N9禽流感疫苗的研究进展

郭琦，廖国阳

摘要：2013年初，中国部分城市和地区出现了禽流感病毒H7N9感染人的病例，截止目前已有超过500人感染H7N9，感染者死亡率约为30%。WHO专家预测，禽流感病毒H7N9可能引起大流行。因此，人用H7N9禽流感疫苗的研发刻不容缓。目前已有多个H7N9疫苗备选株通过了WHO安全性评价，可用于疫苗研发。在此基础上，H7N9灭活疫苗、减毒活疫苗以及重组疫苗均已取得较好的研究结果。本文对人用H7N9禽流感疫苗的研究进展作一综述。

关键词：流感病毒；H7N9；疫苗

来源出版物：中国生物制品学杂志, 2017, 30(2): 210-214

联系邮箱：廖国阳，liaogy@imbcams.com.cn

重组H7N9亚型流感病毒血凝素（HA）的表达及鉴定

孟令楠，任志广，冀显亮，等

摘要：目的：为了获得H7N9HA蛋白，利用昆虫杆状病毒表达系统表达了H7N9HA基因并获得重组H7N9亚型流感病毒HA蛋白。方法：将H7N9亚型流感病毒的HA蛋白基因扩增并克隆到pFastBacⅠ载体中，构建重组穿梭质粒，转染昆虫sf9细胞后获得重组杆状病毒，对大量培养后表达的H7N9HA蛋白进行SDS-PAGE、Western blot和间接免疫荧光检测。分别在0 d和14 d用纯化的表达产物HA蛋白免疫小鼠。结果：测序鉴定重组表达载体构建正确；SDS-PAGE显示纯化的表达蛋白分子质量为67 ku；Western blot分析该蛋白能够被鸡抗流感病毒IgG识别；鸡抗流感病毒抗体间接免疫荧光法测定HA蛋白的表达，在感染HA的昆虫细胞中出现特异性荧光。结论：成功的表达了H7N9的HA蛋白，并且此HA蛋白能成功的诱导小鼠体内的免疫反应，并起到良好的保护作用。

关键词：流感病毒；H7N9HA蛋白；杆状病毒表达系统

来源出版物：中国病原生物学杂志, 2016, 11(5): 401-410

联系邮箱：夏咸柱，xiaxzh@cae.cn

2013—2014年浙江省武义县职业暴露人群及外环境H7N9禽流感病毒监测分析

王晓柳，饶国强，程晓呤，等

摘要：目的：探讨H7N9禽流感的来源及高危因素，为制定科学的防控策略及流感流行预警提供依据。方法：采集2013—2014年浙江省武义县从事销售和屠宰家禽的职业暴露人群血清标本43份，采用血凝抑制实验检测禽流感病毒抗体；采集外环境标本375份，采用实时荧光定量聚合酶链反应方法检测H7N9禽流感病毒核酸，对监测结果进行分析。结果：职业暴露人群H7N9禽流感病毒抗体均为阴性，2014年有6个监测场所检出H7N9禽流感病毒阳性，阳性率为11.11%（6/54），阳性场所分布在3个乡镇。家禽粪便标本、笼具表面涂抹物等标本检出阳性10份，阳性率2.67%（10/375）。结论：武义县禽流感职业暴露人群尚未发现禽流感隐性感染者，在武义县3家活禽和宰杀市场的外环境中检测到H7N9禽流感病毒，提示存在人感染H7N9禽流感病毒的风险。

关键词：职业暴露；外环境；H7N9禽流感；监测

来源出版物：实用预防医学, 2016, 23(6): 712-714

联系邮箱：王晓柳，253525754@qq.com

2014年9—12月中国内地人感染H7N9禽流感疫情流行病学特征分析

周蕾，任瑞琦，张彦平，等

摘要：目的：分析中国大陆地区2014年9—12月人感染H7N9禽流感疫情情况，为防控策略的制定和调整提供科学依据。方法：以我国报告的确诊H7N9禽流感病例为研究对象，用描述性流行病学方法分析病例的时间、空间和人群分布特点。结果：2014年9—12月，我国共确诊人感染H7N9禽流感病例31例，死亡9例，病例数较上年同期增长2.1倍。病例分布在7个省（直辖市），其中13例发生在既往有疫情的县（区），18例发生在新发县（区）。病例的年龄中位数为54岁（7～83岁），男性占48%（15/31）。93.5%的病例在发病前有禽类相关暴露史。结论：近期中国内地人感染H7N9禽流感疫情较去年同期明显增长，部分省份出现地域聚集性，多数病例在发病前有活禽或活禽市场暴露史。近期疫情仍会呈现散发态势，仍会继续出现新发病例和新发省份或地区，减少禽类或活禽市场暴露仍是防控重点。

关键词：人感染H7N9禽流感；流行病学特征；疫情形势

来源出版物：疾病监测, 2015, 30(4): 265-268

联系邮箱：李群，liqun@chinacdc.cn

来源出版物：Epidemiology and Infection, 2017, 145(1):

133-140

联系邮箱：Chen, EF; enfchen@163.com

Estimating risks of inapparent avian exposure for human infection: Avian influenza virus A (H7N9) in Zhejiang Province, China

Ge, E; Zhang, RJ; Li, DK; et al.

Abstract: Inapparent avian exposure was suspected for the sporadic infection of avian influenza A (H7N9) occurring in China. This type of exposure is usually unnoticed and difficult to model and measure. Infected poultry with avian influenza H7N9 virus typically remains asymptomatic, which may facilitate infection through inapparent poultry/bird exposure, especially in a country with widespread practice of backyard poultry. The present study proposed a novel approach that integrated ecological and case-control methods to quantify the risk of inapparent avian exposure on human H7N9 infection. Significant associations of the infection with chicken and goose densities, but not with duck density, were identified after adjusting for spatial clustering effects of the H7N9 cases across multiple geographic scales of neighborhood, community, district and city levels. These exposure risks varied geographically in association with proximity to rivers and lakes that were also proxies for inapparent exposure to avian-related environment. Males, elderly people, and farmers were high-risk subgroups for the virus infection. These findings enable health officials to target educational programs and awareness training in specific locations to reduce the risks of inapparent exposure.

来源出版物：Scientific Reports, 2017, 7: 40016

联系邮箱：Wei, XL; xiaolin.wei@utoronto.ca

In vitro exposure system for study of aerosolized influenza virus

Creager, HM; Zeng, H; Pulit-Penaloza, JA; et al.

Abstract: Infection of adherent cell monolayers using a liquid inoculum represents an established method to reliably and quantitatively study virus infection, but poorly recapitulates the exposure and infection of cells in the respiratory tract that occurs during infection with aerosolized pathogens. To better simulate natural infection in vitro, we adapted a system that generates viral aerosols similar to those exhaled by infected humans to the inoculation of epithelial cell monolayers. Procedures for cellular infection and calculation of exposure dose were developed and tested using viruses characterized by distincttransmission and pathogenicity phenotypes: an HPAI H5N1, an LPAI H7N9, and a seasonal H3N2 virus. While all three aerosolized viruses were highly infectious in a human bronchial epithelial cell line (Calu-3) cultured submerged in media, differences between the viruses were observed in primary human alveolar epithelial cells and in Calu-3 cells cultured at air-liquid interface. This system provides a novel enhancement to traditional in vitro experiments, particularly those focused on the early stages of infection.

关键词：influenza; aerosols; cell culture; viral replication; avian viruses

来源出版物：Virology, 2017, 500: 62-70

联系邮箱：Belser, JA; jax6@cdc.gov

Susceptibility of chickens, quail, and pigeons to an H7N9 human influenza virus and subsequent egg-passaged strains

Uchida, Y; Kanehira, K; Takemae, N; et al.

Abstract: H7N9 human influenza virus A/Anhui/1/2013 (Anhui2013) showed low pathogenicity in chickens, quail, and pigeons, with quail being the most susceptible among the species tested. IVPIE1-1, which was recovered from a dead chicken after intravenous inoculation of Anhui 2013, had broader tissue tropism in chickens than did the original inoculum, as well as amino acid substitutions in the polymerase acidic gene and neuraminidase gene segments, but its pathogenicity was not enhanced. Viruses obtained after passage of Anhui 2013 in 10-and 14-day-old embryonated eggs showed rapid accumulation of amino acid substitutions at the receptor-binding site of the hemagglutinin protein. Two strains obtained through egg passage, 10E4/14E17 and 10E4/10E13, replicated better in intranasally infected chickens than did the original Anhui 2013 strain, yet the new isolates showed low pathogenicity in chickens despite their amino acid substitutions. The increased virus replication in chickens of 10E4/14E17 and 10E4/10E13 was not correlated with temperature-sensitive replication, given that virus replication was suppressed at increased temperatures. The existence of highly susceptible hosts, such as quail, which permit asymptomatic infection, facilitates increased mutation of the virus through amino acid substitution at the receptor-binding site, and this might be one of the mechanisms underlying the prolonged circulation of H7N9 influenza virus.

来源出版物：Archives of Virology, 2017, 162 (1): 103-116

联系邮箱：Saito, T; uchiyu@affrc.go.jp

PB2 substitutions V598T/I increase the virulence of H7N9 influenza A virus in mammals

Hu, M; Yuan, SF; Zhang, K; et al.

Abstract: PB2 is one of the subunits of the influenza A virus (IAV) polymerase complex. By bioinformatics analysis we identified PB2 substitutions at positions 389 and 598 among IAV isolates from humans, which might associate with viral pathogenicity. To evaluate the biological significance of these substitutions, PB2-K389R and -V598T/I mutant viruses of avian H7N9 IAVs were generated by reverse genetics. Compared to the wild type, the mutant viruses displayed an enhanced growth capacity in human and mammalian cells. Meanwhile, they presented increased transcription and replication by producing higher levels of viral mRNA, cRNA and vRNA. Minireplicon assays indicated that the polymerase activity was elevated by these substitutions. Notably, the PB2-V598T/I substitutions substantially increased virus replication and virulence in mice. Together, we demonstrated that the substitutions PB2-V598T/I contributed to higher IAV replication and virulence in mammals, which added to the knowledge of IAV virulence determinants and benefited the surveillance of IAVs.

关键词：influenza A virus; PB2; PB2-K389R; PB2-V598T/I; virulence

来源出版物：Virology, 2017, 501: 92-101

联系邮箱：Chu, H; hinchu@hku.hk

Rapid and sensitive detection of RNA viruses based on reverse transcription loop-mediated isothermal amplification, magnetic nanoparticles, and chemiluminescence

Wang, JH; Lu, P; Yan, JN; et al.

Abstract: RNA viruses, particularly, the highly pathogenic avian influenza (HPAI) virus, pose serious health concerns, and cause huge economic losses worldwide. Diagnostic tools for the early detection of these deadly RNA viruses are urgently needed to implement treatment and disease control strategies. Conventional reverse transcription polymerase chain reaction (RT-PCR)-based chemiluminescent (RT-PCR-CL) detection is frequently used for the diagnosis of viral infections. However, the requirements for expensive PCR machines and longer thermocycling times are significant drawbacks. In thisstudy, we propose a method based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) combined with chemiluminescence (CL) to detect H7N9 virus. The proposed method does not require any expensive instruments, and processing time is remarkably shortened compared to that of RT-PCR-CL. Since several factors including RT-LAMP temperature, probe concentration, hybridization temperature, and hybridization duration might affect the CL signal, each of these parameters was investigated and optimized. One thousand copies/mL of H7N9 RNA were detectable using the optimized RT- LAMP-CL method. The detection time was significantly reduced by using RT-LAMP, in comparison with conventional RT-PCR-CL. This technique holds great promise for viral detection and diagnosis, especially with regard to avian influenza virus.

来源出版物：Journal of Biomedical Nanotechnology, 2016, 12(4): 710-716

联系邮箱：Li, ZY; sslb_112@hotmail.com

Species difference in ANP32A underlies influenza A virus polymerase host restriction

Long, JS; Giotis, ES; Moncorge, O; et al.

Abstract: Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal lowcomplexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2 (E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co-opted to support influenza virus replication and is a candidate host target for novel antivirals.

来源出版物：Nature, 2016, 529(7584): 101-104

联系邮箱：Barclay, WS; w.barclay@imperial.ac.uk

Both neutralizing and non-neutralizing human H7N9 influenza vaccine-induced monoclonal antibodies confer protection

Dunand, CJH; Leon, PE; Huang, M; et al.

Abstract: Pathogenic H7N9 avian influenza viruses continue to represent a public health concern, and several candidate vaccines are currently being developed. It is vital to assess if protective antibodies are induced following vaccination and to characterize the diversity of epitopes targeted. Here we characterized the binding and functional properties of twelve H7-reactive human antibodies induced by a candidate A/Anhui/1/2013 (H7N9) vaccine. Both neutralizing and non-neutralizing antibodies protected mice in vivo during passive transfer challenge experiments. Mapping the H7 hemagglutinin antigenic sites by generating escape mutant variants against the neutralizing antibodies identified unique epitopes on the head and stalk domains. Further, the broadly cross-reactive non-neutralizing antibodies generated in this study were protective through Fc-mediated effector cell recruitment. These findings reveal important properties of vaccine-induced antibodies and provide a better understanding of the human monoclonal antibody response to influenza in the context of vaccines.

来源出版物：Cell Host & Microbe, 2016, 19(6): 800-813

联系邮箱：Wilson, PC; florian.krammer@mssm.edu

PB2-588 V promotes the mammalian adaptation of H10N8, H7N9 and H9N2 avian influenza viruses

Xiao, CC; Ma, WJ; Sun, N; et al.

Abstract: Human infections with avian influenza H7N9 or H10N8 viruses have been reported in China, raising concerns that they might cause human epidemics and pandemics. However, how these viruses adapt to mammalian hosts is unclear. Here we show that besides the commonly recognized viral polymerase subunit PB2 residue 627 K, other residues including 87E, 292 V, 340 K, 588 V, 648 V, and 676 M in PB2 also play critical roles inmammalian adaptation of the H10N8 virus. The avian-origin H10N8, H7N9, and H9N2 viruses harboring PB2-588V exhibited higher polymerase activity, more efficient replication in mammalian and avian cells, and higher virulence in mice when compared to viruses with PB2-588 A. Analyses of available PB2 sequences showed that the proportion of avian H9N2 or human H7N9 influenza isolates bearing PB2-588 V has increased significantly since 2013. Taken together, our results suggest that the substitution PB2-A588V may be a new strategy for an avian influenza virus to adapt mammalian hosts.

来源出版物：Scientific Reports, 2016, 6, 19474

联系邮箱：Qi, WB; qiwenbao@scau.edu.cn

Broadly-reactive neutralizing and non-neutralizing antibodies directed against the H7 influenza virus hemagglutinin reveal divergent mechanisms of protection

Tan, GS; Leon, PE; Albrecht, RA; et al.

Abstract: In the early spring of 2013, Chinese health authorities reported several cases of H7N9 influenza virus infections in humans. Since then the virus has established itself at the human-animal interface in Eastern China and continues to cause several hundred infections annually. In order to characterize the antibody response to the H7N9 virus we generated several mouse monoclonal antibodies against the hemagglutinin of the A/Shanghai/1/13 (H7N9) virus. Of particular note are two monoclonal antibodies, 1B2 and 1H5, that show broad reactivity to divergent H7 hemagglutinins. Monoclonal antibody 1B2 binds to viruses of the Eurasian and North American H7 lineages and monoclonal antibody 1H5 reacts broadly to virus isolates of the Eurasian lineage. Interestingly, 1B2 shows broad hemagglutination inhibiting and neutralizing activity, while 1H5 fails to inhibit hemagglutination and demonstrates no neutralizing activity in vitro. However, both monoclonal antibodies were highly protective in an in

vivo passive transfer challenge model in mice, even at low doses. Experiments using mutant antibodies that lack the ability for Fc/Fc-receptor and Fc/complement interactions suggest that the protection provided by mAb 1H5 is, at least in part, mediated by the Fc-fragment of the mAb. These findings highlight that a protective response to a pathogen may not only be due to neutralizing antibodies, but can also be the result of highly efficacious non-neutralizing antibodies not readily detected by classical in vitro neutralization or hemagglutination inhibition assays. This is of interest because H7 influenza virus vaccines induce only low hemagglutination inhibiting antibody titers while eliciting robust antibody titers as measured by ELISA. Our data suggest that these binding but non-neutralizing antibodies contribute to protection in vivo.

来源出版物：PLoS Pathog, 2016, 12(4): e1005578

联系邮箱：Krammer, F; Gene.Tan@mssm.edu

Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus

Pu, J; Wang, SG; Yin, YB; et al.

Abstract: The emergence of human infection with a novel H7N9 influenza virus in China raises a pandemic concern. Chicken H9N2 viruses provided all six of the novel reassortant's internal genes. However, it is not fully understood how the prevalence and evolution of these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that over more than 10 y of cocirculation of multiple H9N2 genotypes, a genotype (G57) emerged that had changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens in China, caused widespread outbreaks in 2010-2013 before the H7N9 viruses emerged in humans, and finally provided all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential.

来源出版物：Proceedings of the National Academy of Sciences, 2015, 112(2): 548-553

联系邮箱：Liu, JH, S; ljh@cau.edu.cn

Dissemination, divergence and establishment of H7N9 influenza viruses in China

Lam, TTY; Zhou, BP; Wang, J; et al.

Abstract: Since 2013 the occurrence of human infections by a novel avian H7N9 influenza virus in China has demonstrated the continuing threat posed by zoonotic pathogens. Although the first outbreak wave that was centred on eastern China was seemingly averted, human infections recurred in October 2013. It is unclear how the H7N9 virus re-emerged and how it will develop further; potentially it may become a long-term threat to publichealth. Here we show that H7N9 viruses have spread from eastern to southern China and become persistent in chickens, which has led to the establishment of multiple regionally distinct lineages with different reassortant genotypes. Repeated introductions of viruses from Zhejiang to other provinces and the presence of H7N9 viruses at live poultry markets have fuelled the recurrence of human infections. This rapid expansion of the geographical distribution and genetic diversity of the H7N9 viruses poses a direct challenge to current disease control systems. Our results also suggest that H7N9 viruses have become enzootic in China and may spread beyond the region, following the pattern previously observed with H5N1 and H9N2 influenza viruses.

来源出版物：Nature, 2015, 522(7554): 102-105

联系邮箱：Guan, Y; yguan@hku.hk

Assessment of the internal genes of influenza A (H7N9) virus contributing to high pathogenicity in mice

Bi, YH; Xie, Q; Zhang, S; et al.

Abstract: The recently identified H7N9 influenza A virus has caused severe economic losses and worldwide public concern. Genetic analysis indicates that its six internal genes all originated from H9N2 viruses. However, the H7N9 virus is more highly pathogenic in humans than H9N2, which suggests that the internal genes of H7N9 have mutated. To analyze which H7N9 virus internal genes contribute to its high pathogenicity, a series of reassortants was generated by reverse genetics, with each virus containing a single internal gene of the typical A/Anhui/1/2013 (H7N9) (AH-H7N9) virus in the genetic background of the A/chicken/Shandong/lx1023/2007 (H9N2) virus. The replication ability, polymerase activity, and pathogenicity of these viruses were then evaluated in vitro and in vivo. These recombinants displayed high genetic compatibility, and the H7N9-derived PB2, M, and NP genes were identified as the virulence genes for the reassortants in mice. Further investigation confirmed that the PB2 K627 residue is critical for the high pathogenicity of the H7N9 virus and the reassortant containing the H7N9-derived PB2 segment (H9N2-AH/PB2). Notably, the H7N9-derived PB2 gene displayed greater compatibility with the H9N2 genome than that of H7N9, endowing the H9N2-AH/PB2 reassortant with greater viability and virulence than the parental H7N9 virus. In addition, the H7N9 virus, with the exception of the H9N2 reassortants, could effectively replicate in human A549 cells. Our results indicate that PB2, M, and NP are the key virulence genes, together with the surface hemagglutinin (HA) and neuraminidase (NA) proteins, contributing to the high infectivity of the H7N9 virus in humans. IMPORTANCE: To date, the novel H7N9 influenza A virus has caused 437 human infections, with approximately 30% mortality. Previous work has primarily focused on the two viral surface proteins, HA and NA, but the contribution of the six internal genes to the high pathogenicity of H7N9 has not been systematically studied. Here, the H9N2 virus was used as a genetic backbone to evaluate the virulence genes of H7N9 virus in vitro and in vivo. Our data indicate that the PB2, M, and NP genes play important roles in viral infection in mice and, together with HA and NA, contribute to the high infectivity of the H7N9 virus in humans.

来源出版物：Journal of Virology, 2015, 89(1): 2-13

联系邮箱：Gao, GF; Gaof@im.ac.cn

Differences in the epidemiology of human cases of avian influenza A (H7N9) and A (H5N1) viruses infection

Qin, Y; Horby, PW; Tsang, TK; et al.

Abstract: Background: The pandemic potential of avian influenza viruses A(H5N1) and A(H7N9) remains an unresolved but critically important question. Methods: We compared the characteristics of sporadic and clustered cases of human H5N1 and H7N9 infection, estimated the relative risk of infection in blood-related contacts, and the reproduction number (R). Results: We assembled and analyzed data on 720 H5N1 cases and 460 H7N9 cases up to 2 November 2014. The severity and average age of sporadic/index cases of H7N9 was greater than secondary cases (71% requiring intensive care unit admission vs 33%, P = 0.007; median age 59 years vs 31, P ＜ 0.001). We observed no significant differences in the age and severity between sporadic/index and secondary H5N1 cases. The upper limit of the 95% confidence interval (CI) for Rwas 0.12 for H5N1 and 0.27 for H7N9. A higher proportion of H5N1 infections occurred in clusters (20%) compared to H7N9 (8%). The relative risk of infection in blood-related contacts of cases compared to unrelated contacts was 8.96 for H5N1 (95% CI, 1.30, 61.86) and 0.80 for H7N9 (95% CI, .32, 1.97). Conclusions: The results are consistent withan ascertainment bias towards severe and older cases for sporadic H7N9 but not for H5N1. The lack of evidence for ascertainment bias in sporadic H5N1 cases, the more pronounced clustering of cases, and the higher risk of infection in blood-related contacts, support the hypothesis that susceptibility to H5N1 may be limited and familial. This analysis suggests the potential pandemic risk may be greater for H7N9 than H5N1.

来源出版物：Clinical Infectious Diseases, 2015, 61(4): 563-571

联系邮箱：Yu, HJ; yuhj@chinacdc.cn

Characterization of drug-resistant influenza A (H7N9) variants isolated from an oseltamivir-treated patient in Taiwan

Marjuki, H; Mishin, VP; Chesnokov, AP; et al.

Abstract: Background: Patients contracting influenza A(H7N9) infection often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for influenza A(H7N9) is limited. Methods: Four NA variants of A/Taiwan/1/2013(H7N9) virus containing a single substitution (NA-E119V, NAI222K, NA-I222R, or NA-R292K) recovered from an oseltamivir-treated patient were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice, and ferrets. Results: NA-R292K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119V, NA-I222K, and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA -R292K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of NA-I222K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NAR292K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract but produced only mild illness. NA-R292K virus, showed reduced replicative fitness in this animal model. Conclusions: Our data highlight challenges in assessment of the replicative fitness of H7N9 NA variants that emerged in NAI-treated patients.

关键词：influenza virus; H7N9; oseltamivir; peramivir; R292K; E119V; I222K; I222R; mice; ferrets

来源出版物：Journal of Infectious Diseases, 2015, 211(2): 249-257

联系邮箱：Gubareva, LV; lgubareva@cdc.gov

编辑：王微

Quantitative risk analysis of the novel H7N9 virus in environments associated with H9 avian influenza virus, Zhejiang province, China

He, F; Lin, JF; Wang, XY; et al.

H9 avian influenza virus played a key role during generation of the novel H7N9 virus. A surveillance programme was conducted to assess the H9 virus in relation to the risk of H7N9 virus contamination in the environment. Risk of H7N9 virus contamination in the presence of H9 virus was higher than without (adjusted odds ratio 449, 95% confidence interval 379-531). Adjusted odds ratios of the H7N9 virus associated with co-presence of H9 virus and interacting factors were 493 (rural vs. urban area), 4680 (live poultry markets vs. other premises), 686 (Huzhou vs. Hangzhou prefecture), 4067 (year 2015 vs. 2013), and 963 (sewage from cleaning poultry vs. poultry faeces). Regular surveillance on gene variability of H7N9 and H9 viruses should be conducted and extra measures are needed to reduce co-circulation of H7N9 and H9 viruses in the environment.