Origin and Characteristics of Internal Genes Affect Infectivity of the Novel Avian-Origin Influenza A (H7N9) Virus

Yan, Feng; Mao, Haiyan; Xu, Changping; Jiang, Jianmin; Chen, Yin; Yan, Juying; Gao, Jian; Li, Zhen; Xia, Shichang; Lu, Yi‐Yu

doi:10.1371/journal.pone.0081136

Cited by 21 publications

(14 citation statements)

References 30 publications

(51 reference statements)

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“…NS2, also called NEP, functions as a mediator to export the viral RNPs (vRNPs) from the host cell nucleus and is able to confer a significant replicative advantage during mammalian adaptation of an HPAIV (35). Genetic analyses show that the internal genes of the H7N9 virus share high degrees of homology to those of H9N2 viruses (8,12,13). However, H9N2 rarely infects humans, with the occasional human cases only presenting mild respiratory tract signs (6).…”

Section: Discussionmentioning

confidence: 99%

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Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Xie

Zhang

et al. 2015

J Virol

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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. IMPORTANCETo 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. A vian influenza virus (AIV) is an enveloped, single-stranded negative-sense RNA virus that belongs to the influenza A genus of the Orthomyxoviridae family. The AIV genome is comprised of eight gene segments: hemagglutinin (HA), neuraminidase (NA), basic polymerase 2 (PB2), basic polymerase 1 (PB1), acidic polymerase (PA), nucleoprotein (NP), matrix (M), and nonstructural protein (NS). Based on the antigenic properties of the HA (H1 to H16) and NA (N1 to N9) surface glycoproteins, as well as two recently discovered bat-derived H17N10 and H18N11 influenza-like genomes (1), AIV can be further divided into subtypes.AIV is generally considered species specific and rarely crosses the species barrier to infect mammals and humans (2). However...

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Section: Discussionmentioning

confidence: 99%

“…In contrast to H5N1, H9 subtype AIVs are generally considered to be low-pathogenicity viruses, causing mild disease among domestic poultry and wild birds (8). Human infections with H9N2 AIV are rarely reported, with the virus causing only mild influenzalike symptoms (6).…”

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confidence: 99%

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Xie

Zhang

et al. 2015

J Virol

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“…As noted above, several influenza A viruses that emerged in recent years possess genes encoding internal proteins which originally were derived from H9N2 viruses by reassortment (Guan et al, 1999;Choi et al, 2004;Feng et al, 2013;Gao et al, 2013;Chen et al, 2014;Qi et al, 2014). It was therefore of interest to analyse the compatibility of the polymerase subunits of the H9N2 virus with the subunits of other strains.…”

Section: Discussionmentioning

confidence: 99%

PB2 subunit of avian influenza virus subtype H9N2: a pandemic risk factor

Sediri

Thiele

Schwalm

et al. 2016

Journal of General Virology

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Avian influenza viruses of subtype H9N2 that are found worldwide are occasionally transmitted to humans and pigs. Furthermore, by co-circulating with other influenza subtypes, they can generate new viruses with the potential to also cause zoonotic infections, as observed in 1997 with H5N1 or more recently with H7N9 and H10N8 viruses. Comparative analysis of the adaptive mutations in polymerases of different viruses indicates that their impact on the phylogenetically related H9N2 and H7N9 polymerases is higher than on the non-related H7N7 and H1N1pdm09 polymerases. Analysis of polymerase reassortants composed of subunits of different viruses demonstrated that the efficient enhancement of polymerase activity by H9N2-PB2 does not depend on PA and PB1. These observations suggest that the PB2 subunit of the H9N2 polymerase has a high adaptive potential and may therefore be an important pandemic risk factor.

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“…As of July 8, 2014, there have been 435 cases of human infection caused by the H7N9 virus in twelve provinces and two municipalities in China [3]. The novel H7N9 virus is a triple reassortant virus in which the hemagglutinin (HA) and neuraminidase (NA) genes originated from avian influenza viruses of duck and migratory bird origin, respectively, while the six internal genes are closely related to two different groups of H9N2 avian influenza viruses from chickens [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Evaluation and application of a one-step duplex real-time reverse transcription polymerase chain reaction assay for the rapid detection of influenza A (H7N9) virus from poultry samples

Bao

Shi

et al. 2015

Arch Virol

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In China, a novel reassortant influenza A (H7N9) virus, which has caused 435 cases of human infection, has recently emerged. Most cases of human infections with the H7N9 virus are known to be associated with a poultry farm and live-poultry markets. In this study, a one-step duplex real-time reverse transcription polymerase chain reaction (RRT-PCR) assay was developed for the simultaneous detection of the hemagglutinin (HA) and neuraminidase (NA) genes of the H7N9 virus for effective surveillance and early diagnosis of cases from clinical samples collected from live-poultry markets or poultry farms. The detection limit of this assay was as low as 0.1 EID50 of H7N9 viruses, which is similar to the detection limit of the real-time RT-PCR assay released by the Word Health Organization. The coefficients of variation (CVs) of both inter-assay and intra-assay reproducibility were less than 1.55 %, showing good reproducibility. No cross-reactivity was observed with RNA of other subtypes of influenza virus or other avian respiratory viruses. The assay can effectively detect H7N9 influenza virus RNA from multiple sources, including chickens, pigeons, ducks, humans, and the environment. Furthermore, the RRT-PCR assay was evaluated with more than 700 clinical samples collected from live-poultry markets and 120 experimentally infected chicken samples. Together, these results indicate that the duplex RRT-PCR assay is a specific, sensitive, and efficient diagnostic method for the epidemiological surveillance and diagnosis of H7N9 virus from different sources, particularly poultry samples.

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Origin and Characteristics of Internal Genes Affect Infectivity of the Novel Avian-Origin Influenza A (H7N9) Virus

Cited by 21 publications

References 30 publications

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

PB2 subunit of avian influenza virus subtype H9N2: a pandemic risk factor

Evaluation and application of a one-step duplex real-time reverse transcription polymerase chain reaction assay for the rapid detection of influenza A (H7N9) virus from poultry samples

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