The PA Protein Directly Contributes to the Virulence of H5N1 Avian Influenza Viruses in Domestic Ducks

Song, Jianzhong; Feng, Huapeng; Xu, Jing; Zhao, Dongming; Shi, Jianzhong; Li, Yanbing; Deng, Guohua; Jiang, Yongping; Li, Xuyong; Zhu, Ping; Guan, Yuntao; Bu, Zhigao; Kawaoka, Yoshihiro; Chen, Hualan

doi:10.1128/jvi.01975-10

Cited by 115 publications

(120 citation statements)

References 44 publications

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“…This implies that the evolution of a LPAI virus to a HPAI virus must involve additional changes in the other gene segments. For instance, PB2, PB1, and NP (10) genes have all been shown to contribute to the virulence of HPAI H5N1 viruses in chickens and the PA gene to virulence in ducks (11).…”

Section: Importancementioning

confidence: 99%

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Diederich

Berhane

Embury-Hyatt

et al. 2015

J Virol

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Although a polybasic HA 0 cleavage site is considered the dominant virulence determinant for highly pathogenic avian influenza (HPAI) H5 and H7 viruses, naturally occurring virus isolates possessing a polybasic HA 0 cleavage site have been identified that are low pathogenic in chickens. In this study, we generated a reassortant H5N3 virus that possessed the hemagglutinin (HA) gene from H5N1 HPAI A/swan/Germany/R65/2006 and the remaining gene segments from low pathogenic A/chicken/British Columbia/CN0006/2004 (H7N3). Despite possessing the HA 0 cleavage site GERRRKKR/GLF, this rH5N3 virus exhibited a low pathogenic phenotype in chickens. Although rH5N3-inoculated birds replicated and shed virus and seroconverted, transmission to naive contacts did not occur. To determine whether this virus could evolve into a HPAI form, it underwent six serial passages in chickens. A progressive increase in virulence was observed with the virus from passage number six being highly transmissible. Whole-genome sequencing demonstrated the fixation of 12 nonsynonymous mutations involving all eight gene segments during passaging. One of these involved the catalytic site of the neuraminidase (NA; R293K) and is associated with decreased neuraminidase activity and resistance to oseltamivir. Although introducing the R293K mutation into the original low-pathogenicity rH5N3 increased its virulence, transmission to naive contact birds was inefficient, suggesting that one or more of the remaining changes that had accumulated in the passage number six virus also play an important role in transmissibility. Our findings show that the functional linkage and balance between HA and NA proteins contributes to expression of the HPAI phenotype. IMPORTANCETo date, the contribution that hemagglutinin-neuraminidase balance can have on the expression of a highly pathogenic avian influenza virus phenotype has not been thoroughly examined. Reassortment, which can result in new hemagglutinin-neuraminidase combinations, may have unpredictable effects on virulence and transmission characteristics of a virus. Our data show the importance of the neuraminidase in complementing a polybasic HA 0 cleavage site. Furthermore, it demonstrates that adaptive changes selected for during the course of virus evolution can result in unexpected traits such as antiviral drug resistance.A vian influenza viruses (AIV) belong to the genus Influenzavirus A in the family Orthomyxoviridae. Although wild waterfowl are considered the natural reservoir for all influenza A viruses, sporadic transmission to poultry and mammals can result in viruses that are adapted to a new host. The roles that the different viral genes play in this process, especially as it relates to tropism and virulence for domestic poultry species, are still not well understood.Influenza A viruses contain a negative-sense, single-stranded, eight-segmented RNA genome that codes for at least 11 proteins. Viruses are categorized based on the hemagglutinin (HA) and neuraminidase (NA) envelope glycoproteins. Sixt...

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Section: Importancementioning

confidence: 99%

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Diederich

Berhane

Embury-Hyatt

et al. 2015

J Virol

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“…The virus also causes a serious and frequently fatal illness in humans who are in contact with infected birds, but the transmission between humans is limited (Claas et al, 1998;Subbarao et al, 1998;Yen et al, 2007;Yuen et al, 1998). Several lines of evidence indicate that the threat of an H5N1 pandemic is real, and that careful planning is necessary to reduce the public health impact of H5N1 AIV infection (Gao et al, 2009;Li & Chen, 2014;Song et al, 2011). Recent human isolates resistant to adamantanes and neuraminidase inhibitors and the difficulty associated with vaccine production against H5N1 AIV mutants illustrate the need for additional research on the epidemiology and biology of H5N1 influenza virus (Proença-Mó dena et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Role of stem glycans attached to haemagglutinin in the biological characteristics of H5N1 avian influenza virus

Zhang¹,

Chen²,

Yang³

et al. 2015

Journal of General Virology

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There are three conserved N-linked glycosites, namely, Asn10, Asn23 and Asn286, in the stem region of haemagglutinin (HA) in H5N1 avian influenza viruses (AIVs). To understand the effect of glycosylation in the stem domain of HA on the biological characteristics of H5N1 AIVs, we used site-directed mutagenesis to generate different patterns of stem glycans on the HA of A/Mallard/ Huadong/S/2005. The results indicated that these three N-glycans were dispensable for the generation of replication-competent influenza viruses. However, when N-glycans at Asn10 plus either Asn23 or Asn268 were removed, the cleavability of HA was almost completely blocked, leading to a significant decrease of the growth rates of the mutant viruses in MDCK and CEF cells in comparison with that of the WT virus. Moreover, the mutant viruses lacking these oligosaccharides, particularly the N-glycan at Asn10, revealed a significant decrease in thermostability and pH stability compared with the WT virus. Interestingly, the mutant viruses induced a lower level of neutralizing antibodies against the WT virus, and most of the mutant viruses were more sensitive to neutralizing antibodies than the WT virus. Taken together, these data strongly suggest that the HA stem glycans play a critical role in HA cleavage, replication, thermostability, pH stability, and antigenicity of H5N1 AIVs.

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“…Various subtypes of AIV have been isolated from ducks, including the two accepted public health threats, i.e., H5N1 and H9N2 viruses (22)(23)(24)(25)(26)(27). Domestic ducks can carry highly pathogenic H5N1 influenza virus yet remain healthy (22,28,29); however, in some cases, the virus can kill them (30)(31)(32). In Hong Kong in the 1970s and 1980s, H9 influenza viruses were detected only in apparently healthy ducks (33).…”

mentioning

confidence: 99%

Complex Reassortment of Multiple Subtypes of Avian Influenza Viruses in Domestic Ducks at the Dongting Lake Region of China

Deng

Dai

Shi

et al. 2013

J Virol

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bTo gain insight into the ecology of avian influenza viruses (AIV), we conducted active influenza virus surveillance in domestic ducks on farms located on the flyway of migratory birds in the Dongting Lake region of Hunan Province, China, from winter 2011 until spring 2012. Specimens comprising 3,030 duck swab samples and 1,010 environmental samples were collected from 101 duck farms. We isolated AIV of various HA subtypes, including H3, H4, H5, H6, H9, H10, H11, and H12. We sequenced the entire coding sequences of the genomes of 28 representative isolates constituting 13 specific subtypes. When the phylogenetic relationships among these isolates were examined, we observed that extensive reassortment events had occurred. Among the 28 Dongting Lake viruses, 21 genotypes involving the six internal genes were identified. Furthermore, we identified viruses or viral genes introduced from other countries, viral gene segments of unknown origin, and a novel HA/NA combination. Our findings emphasize the importance of farmed domestic ducks in the Dongting Lake region to the genesis and evolution of AIV and highlight the need for continued surveillance of domestic ducks in this region.

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The PA Protein Directly Contributes to the Virulence of H5N1 Avian Influenza Viruses in Domestic Ducks

Cited by 115 publications

References 44 publications

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Role of stem glycans attached to haemagglutinin in the biological characteristics of H5N1 avian influenza virus

Complex Reassortment of Multiple Subtypes of Avian Influenza Viruses in Domestic Ducks at the Dongting Lake Region of China

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The PA Protein Directly Contributes to the Virulence of H5N1 Avian Influenza Viruses in Domestic Ducks

Cited by 115 publications

References 44 publications

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA 0 Cleavage Site

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA 0 Cleavage Site

Role of stem glycans attached to haemagglutinin in the biological characteristics of H5N1 avian influenza virus

Complex Reassortment of Multiple Subtypes of Avian Influenza Viruses in Domestic Ducks at the Dongting Lake Region of China

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Product

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Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site

Hemagglutinin-Neuraminidase Balance Influences the Virulence Phenotype of a Recombinant H5N3 Influenza A Virus Possessing a Polybasic HA ₀ Cleavage Site