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. 2022 Dec;11(1):1174-1185.
doi: 10.1080/22221751.2022.2063076.

Novel H5N6 reassortants bearing the clade 2.3.4.4b HA gene of H5N8 virus have been detected in poultry and caused multiple human infections in China

Wenli Gu  1 , Jianzhong Shi  1 , Pengfei Cui  1 , Cheng Yan  1 , Yaping Zhang  1 , Congcong Wang  1 , Yuancheng Zhang  1 , Xin Xing  1 , Xianying Zeng  1 , Liling Liu  1 , Guobin Tian  1 , Yasuo Suzuki  2 , Chengjun Li  1   3 , Guohua Deng  1 , Hualan Chen  1   3
Affiliations

Novel H5N6 reassortants bearing the clade 2.3.4.4b HA gene of H5N8 virus have been detected in poultry and caused multiple human infections in China

Wenli Gu et al. Emerg Microbes Infect. 2022 Dec.

Abstract

The globally circulating H5N8 avian influenza viruses bearing the clade 2.3.4.4b hemagglutinin (HA) gene are responsible for the loss of more than 33 million domestic poultry since January 2020. Moreover, the H5N8 viruses have reassorted with other avian influenza viruses and formed H5N1, H5N2, H5N3, H5N4, and H5N5 viruses in Europe, Africa, and North America. In this study, we analyzed 15 H5N6 viruses isolated from poultry and seven H5N6 viruses isolated from humans, and found these viruses formed seven different genotypes by deriving the clade 2.3.4.4b HA gene of H5N8 viruses, the neuraminidase of domestic duck H5N6 viruses, and internal genes of different viruses that previously circulated in domestic ducks and wild birds in China. Two of these genotypes (genotype 3 and genotype 6) have caused human infections in multiple provinces. The H5N6 viruses isolated from poultry have distinct pathotypes in mice; some of them replicate systemically and are highly lethal in mice. Although these viruses exclusively bind to avian-type receptors, it is worrisome that they may obtain key mutations that would increase their affinity for human-type receptors during replication in humans. Our study indicates that the novel H5N6 reassortants bearing the clade 2.3.4.4b HA gene of H5N8 viruses were generated through reassortment in domestic ducks and may have spread across a wide area of China, thereby posing a new challenge to the poultry industry and human health. Our findings emphasize the importance of careful monitoring, evaluation, and control of the H5N6 viruses circulating in nature.

Keywords: Avian influenza virus; H5N6; clade2.3.4.4b; evolution; pathogenicity; receptor-binding properties.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Phylogenetic tree of the HA genes of H5 viruses. The Bayesian time-resolved phylogenetic tree of the clade 2.3.4.4 HA gene of 170 H5 viruses, including the 15 novel H5N6 reassortants in this study and 155 representative viruses reported by others. The phylogenetic tree of the HA gene with more complete information is shown in the Supporting Figure S1 and was rooted to A/goose/Guangdong/1/1996 (H5N1). The viral names of the 59 clade 2.3.4.4b HAs are shown in the small tree, in which the novel H5N6 viruses sequenced in this study are shown in red and marked with red dots. The H5N6 viruses isolated from humans are marked with red solid triangles.
Figure 2.
Figure 2.
Phylogenetic analyses of the NA gene and the six internal genes of the H5N6 viruses. Phylogenetic analysis was performed by using the MEGA 7.0 software package, implementing the neighbor-joining method. The tree topology was evaluated by 1,000 bootstrap analyses. (a) The phylogenetic tree of the NA genes of 63 H5N6 viruses was rooted to A/Changsha/1/2014 (H5N6). (b-g) The phylogenetic trees of the PB2, PB1, PA, NP, M, and NS genes were rooted to A/goose/Guangdong/1/1996 (H5N1). The novel H5N6 viruses sequenced in this study are shown in red and marked with red dots. The H5N6 viruses isolated from humans are marked with red solid triangles.
Figure 3.
Figure 3.
Genotypes of the H5N6 viruses and the hosts from which these genotypes were detected. The eight bars represent the eight gene segments (from top to bottom: PB2, PB1, PA, HA, NP, NA, M, and NS), and the colour of the bar indicates the closest donor strain of the gene segment.
Figure 4.
Figure 4.
Receptor-binding properties of the H5N6 and H5N8 viruses bearing the clade 2.3.4.4b HA gene. Binding of the indicated viruses to sialylglycopolymers (α-2,3-sialylglycopolymer, blue; α-2,6-sialylglycopolymer, pink). The data shown are the means of three repeats; the error bars indicate standard deviations.
Figure 5.
Figure 5.
Replication and virulence of H5N6 viruses in mice. (a) Virus titers in organs of mice inoculated intranasally with 106 EID50 of different H5N6 viruses. Three mice from each group were euthanized and their organs were collected on day 3 post-inoculation for virus titration in eggs. Data shown are means ± standard deviations. The dashed lines indicate the lower limit of detection. (b) The death pattern and MLD50 of the indicated viruses.
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Grants and funding

This work was supported by the Laboratory for Lingnan Modern Agriculture Project: [Grant Number NT2021007]; the National Key Research and Development Program of China: [Grant Number 2021YFD1800200, 2021YFC2301700]; the National Natural Science Foundation of China: [Grant Number 31672593, 32192451, 31802191]; the China Agriculture Research System: [Grant Number CARS-41G12].

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