[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
PB2 mutations arising during H9N2 influenza evolution in the Middle East confer enhanced replication and growth in mammals
Yasuha Arai, Norihito Kawashita, Madiha Salah Ibrahim, Emad Mohamed Elgendy, Tomo Daidoji, Takao Ono, Tatsuya Takagi, Takaaki Nakaya, Kazuhiko Matsumoto, Yohei Watanabe
Published: July 2, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1007919 / This is an uncorrected proof.
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.
The G1-like clade of H9N2 influenza viruses can undergo genetic reassortment with other influenza virus subtypes to produce novel zoonotic viruses, such as the Gs/GD lineage H5N1, H7N9, H10N8, and H5N8 viruses. 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. However, little is known about the biological properties of H9N2 viruses in this epicentre of infection. Our data showed that, during about two decades of evolution in nature, G1-like subclade strains evolved to produce strains with appreciably higher replication phenotypes in Central Asia and the Middle East, which led to their expanded host range, including to humans. Therefore, G1-like subclade strains in these areas may accumulate mutations to produce novel viruses and the large gene pool in these areas would enable reassortment with other influenza viruses. This study indicated the need for studies of H9N2 viruses in such areas to monitor their evolutionary dynamics and possible genetic changes.
Citation: Arai Y, Kawashita N, Ibrahim MS, Elgendy EM, Daidoji T, Ono T, et al. (2019) PB2 mutations arising during H9N2 influenza evolution in the Middle East confer enhanced replication and growth in mammals. PLoS Pathog 15(7): e1007919. https://doi.org/10.1371/journal.ppat.1007919
Editor: Adam S. Lauring, University of Michigan, UNITED STATES
Received: March 11, 2019; Accepted: June 14, 2019; Published: July 2, 2019
Copyright: © 2019 Arai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This work was supported by CREST (to KM) from Japan Science and Technology Agency (http://www.jst.go.jp/kisoken/crest/en/index.html; Grant Number JPMJCR15F4), partly by a Grant-in-Aid for Scientific Research B (to YW), Young Scientists B (to YA) and Scientific Research on Innovative Areas (to YW) from Japan Society for the Promotion of Science (https://www.jsps.go.jp/english/index.html; Grant Numbers 15H05295, 18K15171 and 19H04841, respectively), and partly by grants from the Takeda Science Foundation (http://www.takeda-sci.or.jp/; [to YW]), the Heiwa Nakajima Foundation (http://www.hnf.jp/; [to YW]), and a Sasakawa Scientific Research Grant from The Japan Science Society (https://www.jss.or.jp/en/; [to YA]), and partly by the JSPS Core-to-Core Program (https://www.jsps.go.jp/english/e-c2c/index.html; [to TN]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Avian Influenza, H9N2.