A Single-Amino-Acid Substitution in the NS1 Protein Changes the Pathogenicity of H5N1 Avian Influenza Viruses in Mice

Jiao, Peirong; Tian, Guobin; Li, Yanbing; Deng, Guohua; Jiang, Yongping; Liu, Chang; Liu, Weilong; Bu, Zhigao; Kawaoka, Yoshihiro; Chen, Hualan

doi:10.1128/jvi.01698-07

Cited by 405 publications

(262 citation statements)

References 33 publications

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“…The analysis of predicted amino acid sequence for NS1 of Dk/VN/ QB1207/12 showed a five amino acid deletion at positions 80-84 which has been reported to enhance cytokine expression by macrophages [39]. The predicted NS1 amino acid sequence of Dk/VN/QB1207/12 displayed an additional two mutations at S42A and E92D which might also increase virulence of this virus in chicken and mice as well as promoting inhibition of host immune responses as previously described [39,40]. Furthermore, the PDZ binding sequence at the C-terminus of the NS1 protein was ESEV, which may correlate with H5N1 virulence in mammals [41].…”

Section: Genetic Analysismentioning

confidence: 54%

Genetic characterization of an H5N1 avian influenza virus from a vaccinated duck flock in Vietnam

Bui

Ogawa²,

Trinh³

et al. 2014

Virus Genes

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This study reports the genetic characterization of a highly pathogenic avian influenza virus subtype H5N1 isolated from a moribund domestic duck in central Vietnam during 2012. In the moribund duck's flock, within 6 days after vaccination with a commercial H5N1 vaccine (Re-5) to 59-day-old birds, 120 out of 2,000 ducks died. Genetic analysis revealed a substantial number of mutations in the HA gene of the isolate in comparison with the vaccine strains, Re-1 and Re-5. Similar mutations were also found in selected Vietnamese H5N1 strains isolated since 2009. Mutations in the HA gene involved positions at antigenic sites associated with antibody binding and also neutralizing epitopes, with some of the mutations resulting in the modification of N-linked glycosylation of the HA. Those mutations may be related to the escape of virus from antibody binding and the infection of poultry, interpretations which may be confirmed through a reverse genetics approach. The virus also carried an amino acid substitution in the M2, which conferred a reduced susceptibility to amantadine, but no neuraminidase inhibitor resistance markers were found in the viral NA gene. Additional information including vaccination history in the farm and the surrounding area is needed to fully understand the background of this outbreak. Such understanding and expanded monitoring of the H5N1 influenza viruses circulating in Vietnam is an urgent need to provide updated information to improve effective vaccine strain selection and vaccination protocols, aiding disease control, and biosecurity to prevent H5N1 infection in both poultry and humans.

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Section: Genetic Analysismentioning

confidence: 54%

Genetic characterization of an H5N1 avian influenza virus from a vaccinated duck flock in Vietnam

Bui

Ogawa²,

Trinh³

et al. 2014

Virus Genes

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“…In this study, we examined 42 natural isolates of the influenza A virus of the H1N1, H3N1, H3N2, H3N6, H3N8, H4N6, H5N3, H6N2, H7N9, H9N2, and H11N9 subtypes for the presence of the known to date pathogenicity factors that are described in the literature [9,10,12]. Our results showed that markers like the ESEV sequence of the PDZ domain ligand in the NS1 viral protein and changes in the reading frame of the viral protein PB1-F2 (N66S replacement) in the context of the wild duck influenza virus genome are not associated with the virus pathogenicity for mice.…”

Section: Discussionmentioning

confidence: 99%

“…Those changes include the following: appearance of a polybasic sequence in the HA cleavage site of HPAIV [3]; deletion in the stem section of NA [4]; the E627K mutation in the polymerase protein PB2 that increases the rate of virus replication [5][6][7]; substitution of N66S in PB1-F2 protein that accelerates the nuclear transport [8][9][10]; and the substitutions in the nonstructural protein NS1 of HPAIV that lead to the efficient suppression of the host interferon synthesis [7,[11][12][13].…”

Section: Introductionmentioning

confidence: 99%

The use of microarrays for the identification of the origin of genes of avian influenza viruses in wild birds

Heydarov

Nf²,

Boravleva³

et al. 2017

Microbiology Independent Research Journal (MIR Journal)

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Forty-two strains of avian influenza viruses were isolated from the wild waterfowls' feces in the city of Moscow. These viruses, as well as reference strains and some experimental reassortants, were analyzed by microarrays. The microarrays contained 176 probes to the different segments of influenza virus genome. The microarray helps to determine 1) the hemagglutinin and neuraminidase proteins subtype; 2) the primary structure of the C-terminal sequence of the viral NS1 protein, which serves as a ligand for the PDZ domain; 3) the presence of stop codons in the reading frame of PB1-F2 as well as the N66S substitution in the PB1-F2 viral protein; 4) the presence of the polybasic site for hemagglutinin cleavage. The viruses of the H3N1, H3N6, H3N8, H4N6, H1N1, H5N3, and H11N9 subtypes were identified from the group of wild birds' isolates. All isolates contained the ESEV sequence at the C-terminus of the NS1 protein and the full-length reading frame for the PB1-F2 protein. The replacement of N66S in PB1-F2 was found in six strains. However, the presence of the ESEV sequence (ligand of PDZ domain) in the NS1 virus protein and the N66S substitution in PB1-F2 did not lead to the pathogenicity of these viruses for mice. All isolates demonstrated high yield growth in chicken embryos and were infectious and immunogenic for mice, but did not induce any clinical symptoms.

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“…As the functional role of the specific amino acid residues of the NS1 proteins has been primarily studied with human influenza virus strains, we attempted to identify critical amino acids of the H5N1 NS1 protein responsible for virus pathogenicity. The open reading frame (ORF) of the NS1 gene was altered by a single amino acid change, according to previously published studies (Donelan et al, 2003;Jiao et al, 2008). In addition, the C-terminal 4 aa (ESEV) of H5N1 NS1 was replaced with that of H3N2 virus (RSKV) to evaluate the effect of this potential PDZ domain-binding motif on the function of the NS1 protein.…”

Section: Newcastle Disease Virus (Ndv) Is a Member Of The Familymentioning

confidence: 99%

“…Point mutation, truncation or deletions of the NS1 gene of influenza A viruses resulted in enhanced IFNinducing capacity of the virus in vivo and in vitro (Donelan et al, 2003;Ferko et al, 2004;Jiao et al, 2008;Z. Li et al, 2006).…”

mentioning

confidence: 99%

Inhibition of host innate immune responses and pathogenicity of recombinant Newcastle disease viruses expressing NS1 genes of influenza A viruses

Kim

Samal

2010

Journal of General Virology

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The NS1 protein has been associated with the virulence of influenza A viruses. To evaluate the role of the NS1 protein in pathogenicity of pandemic H5N1 avian influenza and H1N1 2009 influenza viruses, recombinant Newcastle disease viruses (rNDVs) expressing NS1 proteins were generated. Expression of the NS1 proteins resulted in inhibition of host innate immune responses (beta interferon and protein kinase R production). In addition, the NS1 proteins were localized predominantly in the nucleus of virus-infected cells. Consequently, expression of the NS1 protein contributed to an increase in pathogenicity of rNDV in chickens. In particular, mutational analysis of H5N1 NS1 protein indicated that both the RNA-binding and effector domains affect virus pathogenicity synergistically. Our study also demonstrated that expression of H1N1/09 NS1 resulted in enhanced replication of rNDV in human cells, indicating that function of the NS1 proteins can be host-species-specific.Influenza A viruses are associated with significant morbidity and mortality, causing worldwide epidemics yearly and pandemics sporadically (Li et al., 2004). The genome of influenza A virus consists of eight RNA segments that encode nine structural proteins and two non-structural proteins, NS1 and PB1-F2 (Palese & Shaw, 2007). The NS1 protein has been identified as a determinant of virulence of influenza A viruses (Bergmann et al., 2000;Donelan et al., 2003). A major function of the NS1 protein is to antagonize host innate immune responses. However, the mechanisms and targets for the NS1 protein vary among influenza A viruses (Kochs et al., 2007). The length of the NS1 protein is strain-specific. The NS1 protein is divided into two distinct functional domains: an N-terminal RNAbinding domain and a C-terminal effector domain for interactions with host cellular proteins. In particular, the RNA-binding domain is highly conserved among influenza A viruses, and three residues in the domain are associated with binding double-stranded RNA (dsRNA). The C-terminal 4 aa of NS1 has been identified as a potential PDZ domain-binding motif that might influence the activity of PDZ domain-containing proteins, which are often involved in cellular signaltransduction pathways (Jackson et al., 2008). Newcastle disease virus (NDV) is a member of the familyParamyxoviridae and has a non-segmented, negative-sense RNA genome consisting of six transcriptional units (39-NP-P-M-F-HN-L-59) (Lamb & Parks, 2007). NDV causes a highly contagious respiratory and neurological disease in chickens (Alexander, 1989). NDV strains are categorized into three pathotypes in chickens: lentogenic (avirulent), mesogenic (moderately virulent) and velogenic (highly virulent) (Panda et al., 2004). In this study, we have used a recombinant mesogenic NDV strain to evaluate the role of pandemic influenza A virus NS1 protein in preventing innate host defences and pathogenicity in chickens. The NS1 genes of H5N1 highly pathogenic avian influenza and pandemic H1N1 2009 influenza (H1N1/09) viruses were ins...

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A Single-Amino-Acid Substitution in the NS1 Protein Changes the Pathogenicity of H5N1 Avian Influenza Viruses in Mice

Cited by 405 publications

References 33 publications

Genetic characterization of an H5N1 avian influenza virus from a vaccinated duck flock in Vietnam

Genetic characterization of an H5N1 avian influenza virus from a vaccinated duck flock in Vietnam

The use of microarrays for the identification of the origin of genes of avian influenza viruses in wild birds

Inhibition of host innate immune responses and pathogenicity of recombinant Newcastle disease viruses expressing NS1 genes of influenza A viruses

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