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

Yasuha Arai,Madiha Salah Ibrahim,Norihito Kawashita,Tatsuya Takagi,Takao Ono,Yohei Watanabe,Tomo Daidoji,Takaaki Nakaya,Kazuhiko Matsumoto,Emad Mohamed Elgendy,Adam S Lauring

doi:10.1371/journal.ppat.1007919

Yasuha Arai, Madiha Salah Ibrahim + Show 9 more

Open Access

https://doi.org/10.1371/journal.ppat.1007919

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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.

Highlights

The avian influenza (AI) virus H9N2 subtype was first identified in South China in 1994 [1]
Since 1998, the G1-like subclade of H9N2 influenza virus has been widely circulating in birds in Central Asia and the Middle East and a number of human cases have been reported
A/duck/Egypt/D1Br/2007 (EG/2007) (H5N1) is an ancestral strain of clade 2.2.1 that is unique to Egypt: most clade 2.2.1 field isolates, including EG/2007, have the PB2-E627K mutation [21]

Summary

Introduction

The avian influenza (AI) virus H9N2 subtype was first identified in South China in 1994 [1]. H9N2 infections cause a decline in egg production, with occasional high mortality in poultry [2]. The internal genes of H9N2 viruses are frequently packaged in zoonotic virus reassortants produced from co-infections by H9N2 and other subtype AI viruses (i.e., H5N1 Gs/GD lineage, H7N9, H10N8, H5N8 and H5N6 viruses) [1, 4,5,6]. This production of various subtype AI viruses containing H9N2 internal genes with their accumulated mutations raises a concern that H9N2 virus may generate novel reassortants and pandemic viruses

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