Double mutations in the H9N2 avian influenza virus PB2 gene act cooperatively to increase viral host adaptation and replication for human infections

2021 ◽  
Vol 102 (6) ◽  
Author(s):  
Emad Mohamed Elgendy ◽  
Yasuha Arai ◽  
Norihito Kawashita ◽  
Ayana Isobe ◽  
Tomo Daidoji ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Polymerase Activity ◽  
Host Adaptation ◽  
Influenza Viruses ◽  
Human Adaptation ◽  
Avian Influenza Viruses ◽  
Human Virus ◽  
H9n2 Avian Influenza Virus ◽  
Human Infections ◽  
Virus Isolates

Avian H9N2 influenza viruses in East Asia are genetically diversified and multiple genotypes (A-W) have been established in poultry. Genotype S strains are currently the most prevalent strains, have caused many human infections and pose a public health threat. In this study, human adaptation mutations in the PB2 polymerase in genotype S strains were identified by database screening. Several PB2 double mutations were identified that acted cooperatively to produce higher genotype S virus polymerase activity and replication in human cells than in avian cells and to increase viral growth and virulence in mice. These mutations were chronologically and phylogenetically clustered in a new group within genotype S viruses. Most of the relevant human virus isolates carry the PB2-A588V mutation together with another PB2 mutation (i.e. K526R, E627V or E627K), indicating a host adaptation advantage for these double mutations. The prevalence of PB2 double mutations in human H9N2 virus isolates has also been found in genetically related human H7N9 and H10N8 viruses. These results suggested that PB2 double mutations in viruses in the field acted cooperatively to increase human adaptation of the currently prevalent H9N2 genotype S strains. This may have contributed to the recent surge of H9N2 infections and may be applicable to the human adaptation of several other avian influenza viruses. Our study provides a better understanding of the human adaptation pathways of genetically related H9N2, H7N9 and H10N8 viruses in nature.

scholarly journals Engineering H5N1 avian influenza viruses to study human adaptation

Nature ◽  
2012 ◽  
Vol 486 (7403) ◽  
pp. 335-340 ◽  
Author(s):  
David M. Morens ◽  
Kanta Subbarao ◽  
Jeffery K. Taubenberger
Keyword(s):  
Avian Influenza ◽  
Influenza Viruses ◽  
Human Adaptation ◽  
Avian Influenza Viruses ◽  
H5n1 Avian Influenza

scholarly journals Adaptation of H9N2 Influenza Viruses to Mammalian Hosts: A Review of Molecular Markers

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 541 ◽  
Author(s):  
Xiangjie Sun ◽  
Jessica A. Belser ◽  
Taronna R. Maines
Keyword(s):  
Animal Models ◽  
Avian Influenza ◽  
Mammalian Cells ◽  
Swine Influenza ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Phenotypic Characterization ◽  
Pandemic Preparedness ◽  
Avian Influenza Viruses ◽  
Eurasian Lineage

As the number of human infections with avian and swine influenza viruses continues to rise, the pandemic risk posed by zoonotic influenza viruses cannot be underestimated. Implementation of global pandemic preparedness efforts has largely focused on H5 and H7 avian influenza viruses; however, the pandemic threat posed by other subtypes of avian influenza viruses, especially the H9 subtype, should not be overlooked. In this review, we summarize the literature pertaining to the emergence, prevalence and risk assessment of H9N2 viruses, and add new molecular analyses of key mammalian adaptation markers in the hemagglutinin and polymerase proteins. Available evidence has demonstrated that H9N2 viruses within the Eurasian lineage continue to evolve, leading to the emergence of viruses with an enhanced receptor binding preference for human-like receptors and heightened polymerase activity in mammalian cells. Furthermore, the increased prevalence of certain mammalian adaptation markers and the enhanced transmissibility of selected viruses in mammalian animal models add to the pandemic risk posed by this virus subtype. Continued surveillance of zoonotic H9N2 influenza viruses, inclusive of close genetic monitoring and phenotypic characterization in animal models, should be included in our pandemic preparedness efforts.

scholarly journals Molecular analysis of avian H7 influenza viruses circulating in Eurasia in 1999–2005: detection of multiple reassortant virus genotypes

2008 ◽  
Vol 89 (1) ◽  
pp. 48-59 ◽  
Author(s):  
Laura Campitelli ◽  
Angela Di Martino ◽  
Domenico Spagnolo ◽  
Gavin J. D. Smith ◽  
Livia Di Trani ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Southern China ◽  
Influenza Viruses ◽  
Avian Influenza Viruses ◽  
Phylogenetic Groups ◽  
Entire Genome ◽  
Domestic Poultry ◽  
Virus Genotypes ◽  
In The Wild ◽  
Human Infections

Avian influenza infections by high and low pathogenicity H7 influenza viruses have caused several outbreaks in European poultry in recent years, also resulting in human infections. Although in some cases the source of H7 strains from domestic poultry was shown to be the viruses circulating in the wild bird reservoir, a thorough characterization of the entire genome of H7 viruses from both wild and domestic Eurasian birds, and their evolutionary relationships, has not been conducted. In our study, we have analysed low pathogenicity H7 influenza strains isolated from wild and domestic ducks in Italy and southern China and compared them with those from reared terrestrial poultry such as chicken and turkey. Phylogenetic analysis demonstrated that the H7 haemagglutinin genes were all closely related to each other, whereas the remaining genes could be divided into two or more phylogenetic groups. Almost each year different H7 reassortant viruses were identified and in at least two different years more than one H7 genotype co-circulated. A recent precursor in wild waterfowl was identified for most of the gene segments of terrestrial poultry viruses. Our data suggest that reassortment allows avian influenza viruses, in their natural reservoir, to increase their genetic diversity. In turn this might help avian influenza viruses colonize a wider range of hosts, including domestic poultry.

scholarly journals The PB1 Gene from H9N2 Avian Influenza Virus Showed High Compatibility and Increased Mutation Rate after Reassorting with a Human H1N1 Influenza Virus

2021 ◽  
Author(s):  
Hongrui Cui ◽  
Guangsheng Che ◽  
Mart CM de Jong ◽  
Xuesong Li ◽  
Qinfang Liu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
H1n1 Virus ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Luciferase Reporter ◽  
Avian Influenza Viruses ◽  
Reassortant Virus ◽  
Rnp Complex ◽  
Reassortant Viruses

Abstract BackgroundReassortment between human and avian influenza viruses (AIV) may result in novel viruses with new characteristics that may threaten human health when causing the next flu pandemic. A particular risk may be posed by avian influenza viruses of subtype H9N2 that are currently massively circulating in domestic poultry in Asia and have been shown to infect humans. In this study, we investigate the characteristics and compatibility of a human H1N1 virus with avian H9N2 derived genes. MethodsThe polymerase activity of the viral ribonucleoprotein (RNP) complex from different reassortments was tested in luciferase reporter assays. Reassortant viruses were generated by reverse genetics in which genes of the human WSN-H1N1 virus (A/WSN/1933) were replaced by genes of the avian A2093-H9N2 virus (A/chicken/Jiangsu/A2093/2011). We replaced both the Hemagglutinin (HA) and Neuraminidase (NA) genes in combination with one of the genes involved in the RNP complex (either PB2, PB1, PA or NP). The growth kinetics and virulence of reassortant viruses were tested on cell lines and mice. The reassortant viruses were then passaged for five generations in MDCK cells and mice lungs. The HA gene of progeny viruses from different passaging paths was analyzed using Next Generation Sequencing (NGS). ResultsWe discovered that the avian PB1 gene increased the polymerase activity of the RNP complex. Reassortant viruses were able to replicate in MDCK and DF1 cells and mice. Analysis of the NGS data showed a higher substitution rate for the PB1-reassortant virus. In particular, for the PB1-reassortant virus, increased virulence for mice was measured by increased body weight loss after infection in mice. ConclusionsThe higher polymerase activity and increased mutation frequency measured for the PB1-reassortant virus suggests that the avian PB1 gene may drive the evolution and adaptation of novel reassortant viruses to the human host. This study provides novel insights in the characteristics of novel viruses that may arise by reassortment of human and avian influenza viruses. Surveillance for infections with H9N2 viruses and the emergence of novel reassortant viruses in humans is important for pandemic preparedness.

scholarly journals A Global Perspective on H9N2 Avian Influenza Virus

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 620 ◽  
Author(s):  
T(homas). P. Peacock ◽  
Joe James ◽  
Joshua E. Sealy ◽  
Munir Iqbal
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Host Range ◽  
Influenza Viruses ◽  
Global Perspective ◽  
Zoonotic Infection ◽  
Avian Influenza Viruses ◽  
H9n2 Avian Influenza Virus ◽  
Global Spread

H9N2 avian influenza viruses have become globally widespread in poultry over the last two decades and represent a genuine threat both to the global poultry industry but also humans through their high rates of zoonotic infection and pandemic potential. H9N2 viruses are generally hyperendemic in affected countries and have been found in poultry in many new regions in recent years. In this review, we examine the current global spread of H9N2 avian influenza viruses as well as their host range, tropism, transmission routes and the risk posed by these viruses to human health.

scholarly journals Human infections with novel reassortant H5N6 avian influenza viruses in China

2017 ◽  
Vol 6 (1) ◽  
pp. 1-2 ◽  
Author(s):  
Ye Zhang ◽  
Minmei Chen ◽  
Yiwei Huang ◽  
Wenfei Zhu ◽  
Lei Yang ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza Viruses ◽  
Avian Influenza Viruses ◽  
Human Infections

scholarly journals Avian Influenza Virus PB1 Gene in H3N2 Viruses Evolved in Humans To Reduce Interferon Inhibition by Skewing Codon Usage toward Interferon-Altered tRNA Pools

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Bartram L. Smith ◽  
Guifang Chen ◽  
Claus O. Wilke ◽  
Robert M. Krug
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Codon Usage ◽  
Avian Influenza Virus ◽  
Influenza A ◽  
Human Cells ◽  
Influenza Viruses ◽  
Human Adaptation ◽  
Influenza A Viruses ◽  
Avian Influenza Viruses

ABSTRACTInfluenza A viruses cause an annual contagious respiratory disease in humans and are responsible for periodic high-mortality human pandemics. Pandemic influenza A viruses usually result from the reassortment of gene segments between human and avian influenza viruses. These avian influenza virus gene segments need to adapt to humans. Here we focus on the human adaptation of the synonymous codons of the avian influenza virus PB1 gene of the 1968 H3N2 pandemic virus. We generated recombinant H3N2 viruses differing only in codon usage of PB1 mRNA and demonstrated that codon usage of the PB1 mRNA of recent H3N2 virus isolates enhances replication in interferon (IFN)-treated human cells without affecting replication in untreated cells, thereby partially alleviating the interferon-induced antiviral state. High-throughput sequencing of tRNA pools explains the reduced inhibition of replication by interferon: the levels of some tRNAs differ between interferon-treated and untreated human cells, and evolution of the codon usage of H3N2 PB1 mRNA is skewed toward interferon-altered human tRNA pools. Consequently, the avian influenza virus-derived PB1 mRNAs of modern H3N2 viruses have acquired codon usages that better reflect tRNA availabilities in IFN-treated cells. Our results indicate that the change in tRNA availabilities resulting from interferon treatment is a previously unknown aspect of the antiviral action of interferon, which has been partially overcome by human-adapted H3N2 viruses.IMPORTANCEPandemic influenza A viruses that cause high human mortality usually result from reassortment of gene segments between human and avian influenza viruses. These avian influenza virus gene segments need to adapt to humans. Here we focus on the human adaptation of the avian influenza virus PB1 gene that was incorporated into the 1968 H3N2 pandemic virus. We demonstrate that the coding sequence of the PB1 mRNA of modern H3N2 viruses enhances replication in human cells in which interferon has activated a potent antiviral state. Reduced interferon inhibition results from evolution of PB1 mRNA codons skewed toward the pools of tRNAs in interferon-treated human cells, which, as shown here, differ significantly from the tRNA pools in untreated human cells. Consequently, avian influenza virus-derived PB1 mRNAs of modern H3N2 viruses have acquired codon usages that better reflect tRNA availabilities in IFN-treated cells and are translated more efficiently.

scholarly journals In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein

2017 ◽  
Vol 214 (5) ◽  
pp. 1239-1248 ◽  
Author(s):  
Christoph M. Deeg ◽  
Ebrahim Hassan ◽  
Pascal Mutz ◽  
Lara Rheinemann ◽  
Veronika Götz ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Transgenic Mice ◽  
Influenza A ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Avian Influenza Viruses ◽  
Species Barrier ◽  
Human Virus ◽  
Adaptive Mutations

Zoonotic transmission of influenza A viruses can give rise to devastating pandemics, but currently it is impossible to predict the pandemic potential of circulating avian influenza viruses. Here, we describe a new mouse model suitable for such risk assessment, based on the observation that the innate restriction factor MxA represents an effective species barrier that must be overcome by zoonotic viruses. Our mouse lacks functional endogenous Mx genes but instead carries the human MX1 locus as a transgene. Such transgenic mice were largely resistant to highly pathogenic avian H5 and H7 influenza A viruses, but were almost as susceptible to infection with influenza viruses of human origin as nontransgenic littermates. Influenza A viruses that successfully established stable lineages in humans have acquired adaptive mutations which allow partial MxA escape. Accordingly, an engineered avian H7N7 influenza virus carrying a nucleoprotein with signature mutations typically found in human virus isolates was more virulent in transgenic mice than parental virus, demonstrating that a few amino acid changes in the viral target protein can mediate escape from MxA restriction in vivo. Similar mutations probably need to be acquired by emerging influenza A viruses before they can spread in the human population.

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