PB2 mutations arising during H9N2 influenza evolution in the Middle East confer enhanced replication and growth in mammals.

Yasuha Arai¹ Norihito Kawashita^2,3 Madiha Salah Ibrahim⁴ Emad Mohamed Elgendy⁴ Tomo Daidoji¹ Takao Ono⁵ Tatsuya Takagi³ Takaaki Nakaya¹ Kazuhiko Matsumoto⁵ Yohei Watanabe¹

Affiliations 5 institutions

Department of Infectious Diseases, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Faculty of Science and Engineering, Kindai University, Osaka, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.

PMID31265471 DOI10.1371/journal.ppat.1007919 Year2019 Journal PLoS pathogens PLoS Pathog Languageeng Statusepublish

Abstract

Avian influenza virus H9N2 has been endemic in birds in the Middle East, in particular in Egypt with multiple cases of human infections since 1998. Despite concerns about the pandemic threat posed by H9N2, little is known about the biological properties of H9N2 in this epicentre of infection. Here, we investigated the evolutionary dynamics of H9N2 in the Middle East and identified phylogeny-associated PB2 mutations that acted cooperatively to increase H9N2 replication/transcription in human cells. The accumulation of PB2 mutations also correlated with an increase in H9N2 virus growth in the upper and lower airways of mice and in virulence. These mutations clustered on a solvent-exposed region in the PB2-627 domain in proximity to potential interfaces with host factors. These PB2 mutations have been found at high prevalence during evolution of H9N2 in the field, indicating that they have provided a selective advantage for viral adaptation to infect poultry. Therefore, continuous prevalence of H9N2 virus in the Middle East has generated a far more fit or optimized replication phenotype, leading to an expanded viral host range, including to mammals, which may pose public health risks beyond the current outbreaks.

Supporting text Virus Host Location

Mutation 209 Animals 1948 Evolution, Molecular 176 Female 289 HEK293 Cells 61 Host Specificity 132 Humans 1440 Influenza A Virus, H9N2 Subtype 71 Influenza, Human 286 Mammals 92 Mice 253 Mice, Inbred BALB C 73 Middle East 7 Models, Molecular 99 Orthomyxoviridae Infections 228 Phylogeny 805 Reassortant Viruses 103 RNA-Dependent RNA Polymerase 49 Viral Proteins 152 Virulence 108 Virus Replication 191 Zoonoses 397 PB2 protein, Influenzavirus A 27

Evidence records

3 total

Experimental Infection

1 records · 1 evidence types

Evidence type Pathogenicity Experiment

1 records

OVE3365 Pathogenicity Experiment

Key finding

PB2 mutations in H9N2 influenza virus increased viral growth in the respiratory tract of mice and enhanced virulence in an experimental infection model.

Virus

Host

Location

Supporting text

The accumulation of PB2 mutations also correlated with an increase in H9N2 virus growth in the upper and lower airways of mice and in virulence.

Method: mouse infection | virus growth quantification | virulence assessment
Experimental system: mouse infection model

Functional Mechanism

1 records · 1 evidence types

Evidence type Molecular Adaptation

1 records

OVE3362 Molecular Adaptation

Key finding

PB2 mutations cooperatively increased H9N2 replication and transcription in human cells.

Virus

Host

Location

Supporting text

identified phylogeny-associated PB2 mutations that acted cooperatively to increase H9N2 replication/transcription in human cells.

Genes or proteins: PB2
Mechanism types: replication adaptation

Genomic Evolution

1 records · 1 evidence types

Evidence type Phylogenetic Evolution

1 records

OVE3361 Phylogenetic Evolution

Key finding

Phylogenetic analysis of H9N2 influenza viruses from the Middle East identified PB2 mutations that emerged during regional evolution and were associated with enhanced replication and adaptation to mammals.

Virus

Host

Location

Supporting text

We investigated the evolutionary dynamics of H9N2 in the Middle East and identified phylogeny-associated PB2 mutations that acted cooperatively to increase H9N2 replication/transcription in human cells.

Genes or proteins: PB2
Analysis methods: phylogenetic analysis | evolutionary dynamics analysis

References

50 references

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