Genetic incompatibilities and reduced transmission in chickens may limit the evolution of reassortants between H9N2 and panzootic H5N8 clade 2.3.4.4 avian influenza virus showing high virulence for mammals

Abstract The unprecedented spread of H5N8- and H9N2-subtype avian influenza virus (AIV) in birds across Asia, Europe, Africa, and North America poses a serious public health threat with a permanent risk of reassortment and the possible emergence of novel virus variants with high virulence in mammals. To gain information on this risk, we studied the potential for reassortment between two contemporary H9N2 and H5N8 viruses. While the replacement of the PB2, PA, and NS genes of highly pathogenic H5N8 by homologous segments from H9N2 produced infectious H5N8 progeny, PB1 and NP of H9N2 were not able to replace the respective segments from H5N8 due to residues outside the packaging region. Furthermore, exchange of the PB2, PA, and NS segments of H5N8 by those of H9N2 increased replication, polymerase activity and interferon antagonism of the H5N8 reassortants in human cells. Notably, H5N8 reassortants carrying the H9N2-subtype PB2 segment and to lesser extent the PA or NS segments showed remarkably increased virulence in mice as indicated by rapid onset of mortality, reduced mean time to death and increased body weight loss. Simultaneously, we observed that in chickens the H5N8 reassortants, particularly with the H9N2 NS segment, demonstrated significantly reduced transmission to co-housed chickens. Together, while the limited capacity for reassortment between co-circulating H9N2 and H5N8 viruses and the reduced bird-to-bird transmission of possible H5N8 reassortants in chickens may limit the evolution of such reassortant viruses, they show a higher replication potential in human cells and increased virulence in mammals.

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Receptor Binding Profiles of Avian Influenza Virus Hemagglutinin Subtypes on Human Cells as a Predictor of Pandemic Potential

Journal of Virology ◽

10.1128/jvi.01822-10 ◽

2010 ◽

Vol 85 (4) ◽

pp. 1875-1880 ◽

Cited By ~ 32

Author(s):

H. Shelton ◽

G. Ayora-Talavera ◽

J. Ren ◽

S. Loureiro ◽

R. J. Pickles ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Receptor Binding ◽

Human Cells ◽

Influenza Virus Hemagglutinin

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Adaptive mutations in PB2 gene contribute to the high virulence of a natural reassortant H5N2 avian influenza virus in mice

Virus Research ◽

10.1016/j.virusres.2015.08.017 ◽

2015 ◽

Vol 210 ◽

pp. 255-263 ◽

Cited By ~ 10

Author(s):

Qunhui Li ◽

Xuan Wang ◽

Zhongtao Sun ◽

Jiao Hu ◽

Zhao Gao ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Adaptive Mutations ◽

High Virulence

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Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

Virulence ◽

10.1080/21505594.2018.1475795 ◽

2018 ◽

Vol 9 (1) ◽

pp. 1092-1111 ◽

Cited By ~ 2

Author(s):

Jiao Hu ◽

Zenglei Hu ◽

Xiaoquan Wang ◽

Min Gu ◽

Zhao Gao ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Deep Sequencing ◽

Mouse Lung ◽

H5n1 Avian Influenza Virus ◽

H5n1 Avian Influenza ◽

High Virulence ◽

Non Coding Rnas

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The PA Subunit of the Influenza Virus Polymerase Complex Affects Replication and Airborne Transmission of the H9N2 Subtype Avian Influenza Virus

Viruses ◽

10.3390/v11010040 ◽

2019 ◽

Vol 11 (1) ◽

pp. 40 ◽

Cited By ~ 1

Author(s):

Mengchan Hao ◽

Shaojie Han ◽

Dan Meng ◽

Rong Li ◽

Jing Lin ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Guinea Pigs ◽

Influenza A ◽

Reverse Genetics ◽

Species Barrier ◽

Airborne Transmission ◽

H9n2 Subtype ◽

Influenza A H1n1

The polymerase acidic (PA) protein is the third subunit of the influenza A virus polymerase. In recent years, studies have shown that PA plays an important role in overcoming the host species barrier and host adaptation of the avian influenza virus (AIV). The objective of this study was to elucidate the role of the PA subunit on the replication and airborne transmission of the H9N2 subtype AIV. By reverse genetics, a reassortant rSD01-PA was derived from the H9N2 subtype AIV A/Chicken/Shandong/01/2008 (SD01) by introducing the PA gene from the pandemic influenza A H1N1 virus A/swine/Shandong/07/2011 (SD07). Specific pathogen-free (SPF) chickens and guinea pigs were selected as the animal models for replication and aerosol transmission studies. Results show that rSD01-PA lost the ability of airborne transmission among SPF chickens because of the single substitution of the PA gene. However, rSD01-PA could infect guinea pigs through direct contact, while the parental strain SD01 could not, even though the infection of rSD01-PA could not be achieved through aerosol. In summary, our results indicate that the protein encoded by the PA gene plays a key role in replication and airborne transmission of the H9N2 subtype AIV.

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Evidence for Avian and Human Host Cell Factors That Affect the Activity of Influenza Virus Polymerase

Journal of Virology ◽

10.1128/jvi.01134-10 ◽

2010 ◽

Vol 84 (19) ◽

pp. 9978-9986 ◽

Cited By ~ 72

Author(s):

Olivier Moncorgé ◽

Manuela Mura ◽

Wendy S. Barclay

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Host Range ◽

Influenza A ◽

Human Cells ◽

Influenza A Viruses ◽

New Host ◽

Range Restriction ◽

Positive Factor

ABSTRACT Typical avian influenza A viruses do not replicate efficiently in humans. The molecular basis of host range restriction and adaptation of avian influenza A viruses to a new host species is still not completely understood. Genetic determinants of host range adaptation have been found on the polymerase complex (PB1, PB2, and PA) as well as on the nucleoprotein (NP). These four viral proteins constitute the minimal set for transcription and replication of influenza viral RNA. It is widely documented that in human cells, avian-derived influenza A viral polymerase is poorly active, but despite extensive study, the reason for this blockade is not known. We monitored the activity of influenza A viral polymerases in heterokaryons formed between avian (DF1) and human (293T) cells. We have discovered that a positive factor present in avian cells enhances the activity of the avian influenza virus polymerase. We found no evidence for the existence of an inhibitory factor for avian virus polymerase in human cells, and we suggest, instead, that the restriction of avian influenza virus polymerases in human cells is the consequence of the absence or the low expression of a compatible positive cofactor. Finally, our results strongly suggest that the well-known adaptative mutation E627K on viral protein PB2 facilitates the ability of a human positive factor to enhance replication of influenza virus in human cells.

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Mammalian ANP32A and ANP32B proteins drive alternative avian influenza virus polymerase adaptations

10.1101/2020.09.03.282384 ◽

2020 ◽

Cited By ~ 1

Author(s):

Thomas. P. Peacock ◽

Carol M. Sheppard ◽

Ecco Staller ◽

Rebecca Frise ◽

Olivia C. Swann ◽

...

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Experimental Evolution ◽

Human Cells ◽

Influenza Viruses ◽

Avian Viruses ◽

Evolution Approach ◽

Influenza Polymerase

AbstractANP32 proteins, which act as influenza polymerase co-factors, vary between birds and mammals. The well-known mammalian adaptation, PB2-E627K, enables influenza polymerase to use mammalian ANP32 proteins. However, some mammalian-adapted influenza viruses do not harbour this adaptation. Here, we show that alternative PB2 adaptations, Q591R and D701N also allow influenza polymerase to use mammalian ANP32 proteins. PB2-E627K strongly favours use of mammalian ANP32B proteins, whereas D701N shows no such bias. Accordingly, PB2-E627K adaptation emerges in species with strong pro-viral ANP32B proteins, such as humans and mice, while D701N is more commonly seen in isolates from swine, dogs and horses where ANP32A proteins are more strongly pro-viral. In an experimental evolution approach, passage of avian viruses in human cells drives acquisition of PB2-E627K, but not when ANP32B is ablated. The strong pro-viral support of ANP32B for PB2-E627K maps to the LCAR region of ANP32B.

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