Abstract
The H3-subtype of avian influenza virus (AIV) is one of the most frequently detected low pathogenic avian influenza virus (LPAIV) subtypes in birds and fowls, causing substantial economic loss to the poultry industry. Most importantly, besides poultry, mammals could also be infected with it, such as swines, canines, equines, felines, and humans, posing a serious public health threat. This allows the virus to persist widely in poultry and wild birds for a long time, where it may mix with other subtypes, providing conditions for viral recombination or reassortment. Currently, the monitoring of H3-subtype AIV is inadequate, and there is a lack of effective prevention and control measures for H3-subtype AIV. Here, the epidemiology, phylogeny, and genetic variation of H3-subtype AIV were analyzed, and nonsynonymous and synonymous substitution rates (dN/dS) were calculated. Through these steps, we aimed to clarify the current epidemiological feature and evolutionary characteristics of H3-subtype AIV, and provide an operative reference for future scientific control of H3-subtype AIV.
1 Introduction
Avian influenza virus (AIV) is a type A influenza virus and one of the most significant zoonotic diseases that poses a severe threat to both the poultry industry and human health worldwide (; ). The AIV genome consists of eight segments of single-stranded negative-sense RNA. Haemagglutinin (HA) and neuraminidase (NA), encoded by segments 4 and 6, respectively, are the main antigenic glycoproteins on the surface of AIV (; ). According to the antigenic differences between HA and NA on its surface, AIV were divided to 18 HA subtypes and 11 NA subtypes (). Except for H17N10 and H18N11, which were isolated from bats (), all other subtypes of influenza A viruses had been identified in wild birds (; ; ; ). Different subtypes of AIV have different degrees of pathogenicity to poultry and mainly divided in highly pathogenic avian influenza (HPAI) and lowly pathogenic avian influenza (LPAI). The former is invoked by some H5 and H7 subtype virus strains, while other AIVs usually show low pathogenicity to poultry.
The H3-subtype AIV exists widely in birds, humans, and other mammals. Although its pathogenicity is low, it has many subtype combinations, a wide distribution and complex biological characteristics (). To date, researchers have discovered a total of nine subtypes of H3NX AIV, with H3N2 and H3N8 as the most frequently detected subtypes in birds and canines. And swine and feline influenza were primarily caused by the H3N2 subtype of the influenza A virus, while equine influenza was mainly caused by the H3N8 influenza A virus. In addition, because of the low pathogenicity of H3-subtype AIV, infected animals generally show no symptoms or mild clinical symptoms, so the impact on the breeding industry and human health is often overlooked, which allows H3-subtype AIV to continue to spread and evolve in nature.
H3-subtype AIV has a higher isolation rate in wild birds than in mammals (including humans), especially in wild waterfowl, which are considered its natural hosts. Domestic ducks are considered an important intermediate host for AIV transmission from wild waterfowl to terrestrial fowl and one crucial determinant influencing the genetic diversity of AIV (, ; ). Avian influenza surveillance data indicate that H3- subtypes of AIV were prevalent in domestic ducks and could be mixed within them, providing good conditions for new subtypes and mutations in genes affecting virulence via antigenic transformation. One report showed that H3N8 in wild birds possessed dual-receptor binding properties in the HA protein, which supports the occurrence of this type of AIV interspecies transmission (). Notably, studies had shown that H3NX AIV has the ability to provide genetic fragments for reassortment in other subtypes of influenza viruses, leading to the production of new highly pathogenic strains and thus to influenza outbreaks (; ; ). The H3-subtype AIV can also undergo recombination to alter its pathogenicity and has the potential to break through the interspecific barrier to infect humans (). Studies have shown that H3N2 influenza in Hong Kong in 1968 was also due to recombination with the human H2N2 virus NA, PB2, PA, NP, M and NS genes, but the population does not have immunity to the new HA and NA, resulting in the rapid spread of the new virus, causing a human flu pandemic (). In April 2022, China notified the WHO of the world’s first known human infection with the H3N8 subtype of avian influenza virus ().
2 Epidemiological features of the AIVs H3-subtype
2.1 Geographic arrangement of the H3-subtype
As of July 2023, the GISAID and NCBI databases included sum total of 12,134 H3-subtype AIV HA sequences, which included 304 H3N1 sequences, 7,532 H3N2 sequences, 51 H3N3 sequences, 10 H3N4 sequences, 34 H3N5 sequences, 38 H3N6 sequences, 24 H3N7 sequences, 4,122 N8 sequences, and 17 H3N9 sequences (Figure 1).
Figure 1
The nine NA subtypes of H3NX were mainly distributed in North America, Asia and Europe. North America includes all 9 H3-subtypes AIV (H3N1-H3N9), Asia and Europe are dominated by H3N1, H3N2, H3N6 and H3N8, South America and Africa are dominated by H3N2 and H3N8, and Oceania includes H3N1, H3N2, H3N5 and H3N8 (Figure 2A). H3-subtype AIV is distributed in all major areas except Antarctica. The Eurasian continent has the widest distribution of H3-subtype AIV (the transmission range included 22 Asian countries and 25 European countries). The country with the highest detection rate of H3-subtype AIV in Asia was China (1,296 strains), followed by Vietnam, Thailand, South Korea, Mongolia and Japan (Figure 2B). The country with the highest detection of H3-subtype AIV in Europe was the United Kingdom, which included 342 strains, followed by Germany, Belgium, Italy, the Netherlands, Russia, France and others (Figure 2C). The United States (6,823 strains) had the highest detection rate of H3-subtype AIV in North America, followed by Canada, Mexico and Guatemala (Figure 2D). H3-subtype AIV was also detected in South America, but the detection rate was low; Argentina had 59 strains, followed by Chile, Brazil, Colombia, Peru and Uruguay (Figure 2E). H3-subtype AIV detection in African countries was lower than that in other places, including Senegal (17 strains), Nigeria (13 strains), Algeria (12 strains), Egypt (8 strains), Zambia (4 strains), Morocco (3 strains) and Niger (2 strains) (Figure 2F). In Oceania, H3-subtype AIV was detected only in Australia and New Zealand (Figure 2G).
Figure 2
2.2 Epidemic of H3-subtype avian influenza in poultry
H3-subtype AIV had the ability to infect various mammalian species, such as swine, canine, feline, equine, and even ferret. In recent years, avian influenza surveillance data have shown that the H3-subtype AIV is one of the main circulating avian influenza subtypes, especially in poultry (with a prevalence of approximately 10.93%, Figure 3). H3-subtype AIV had the highest isolation rate in ducks, at 91.76% (). The H3N2 and H3N8 subtypes are the most important subtypes in poultry in China and are primarily found in southeastern China, roughly the same as the main route of wild bird migration (). Guangdong Province had the highest amount of H3-subtype AIV isolated, with 620 isolates. Shandong, Anhui, Guangxi and other provinces were also found to have a number of H3-subtype AIVs (Figure 4).
Figure 3
Figure 4
Unlike waterfowl, chickens are not the natural hosts of the H3 influenza virus, and chickens infected with H3-subtype AIV are typically symptom-free. However, certain H3-subtype AIV strains have been observed to cause disease in chickens, and recent serological tests on chickens in China confirmed that H3-subtype AIV has spread across a wide geographical area (). It has been proven that live poultry markets (LPMs) are likely the main source of H3-subtype AIV infection in chickens. The conditions of LPMs accelerate the adaptation of AIV to new hosts, and some viruses from wild avian can infect chickens directly without prior adaptation (; ). By July 2023, 503 chicken H3-subtype AIV sequences, 589 duck H3-subtype AIV sequences and 9 goose H3-subtype AIV sequences had been submitted. The prevalence of H3-subtypes AIV in poultry is shown in Figure 5.
Figure 5
2.3 Epidemic of H3-subtype avian influenza in wild birds
Wild birds, particularly wild waterfowl, were considered to be natural hosts of AIV (). There is evidence that wild bird migration was an important route leading to the evolution and recombination of influenza virus and their spread to poultry and mammals (). To date, H3-subtype AIV has been found in many kinds of wild avian species in several nations and regions. There are 2,763 H3-subtype AIV HA sequences from wild birds in the GISAID and NCBI databases. The main isolation species were mallard duck (2,129 strains), turnstone (169 strains) and American black duck (85 strains), with mallard duck as the main host (81%, Figure 6), and H3N8 was the dominant strain, with 7,396 strains detected. Green-headed ducks have strong resistance to influenza virus and mild symptoms upon infection. The virus can be transmitted through direct contact and the respiratory tract during migration, and its secretions and excreta may also cause the virus to spread ().
Figure 6
2.4 Epidemic of H3-subtype avian influenza in mammals
Based on statistics, it has been determined that the H3-subtype of influenza virus is capable of infecting a diverse range of hosts. These include not only avian hosts but also various mammals, such as swine, canine, equine, and even humans (Figure 7). Stable mammalian transmission capacity is one of the prerequisites for the spread of the new influenza virus in the population (; ; ; ; ). In March 1989, isolated an avian-origin H3N8 subtype equine influenza virus from horses with severe respiratory disease in northeast China. In 1998, Zhou et al. detected a triple recombinant H3N2 influenza A virus containing genes from human, classical swine, and avian influenza viruses in North American swine (). Since 2005, there have also been frequent incidents of canine infection with avian-origin H3N2 influenza viruses in South Korea and China (; ). During September to December 2011, 162 spotted seals in New England died after contracting H3N8 subtype AIV, which resulted in severe pneumonia (). A study by Guan et al. in 2019 revealed that the H3N2 subtype of AIV isolated from an LPM in China had the ability to infect mice, replicate efficiently in mice, bind to avian- and human-type receptors, and achieve interspecies respiratory droplet transmission in guinea pigs and ferrets (). Between April 2022 and March 2023, there were three cases of human infection with AIV subtype H3N8 in China with severe respiratory symptoms, and all three human cases were associated with exposure to live poultry (; ; ; ). All these lines of evidence of H3-subtype AIV infecting mammals indicate their superb cross-species transmissibility, which is an enormous problem to farming industry and human health and safety.
Figure 7
3 Cross-species transmission
There are differences in the antigenicity of H3-subtype influenza viruses in different hosts, but according to previous reports, the phenomenon of cross-species transmission also occurs occasionally. There are two major lineages of H3-subtype AIV based on phylogenetic analysis and geographical location: the Eurasian lineage and the North American lineage, which are deeply divided into the human/swine lineage and the avian and equine lineage (Figure 8). Studies have shown that both avian H3 lineages can cross-species to infect swine and canines, however, the Eurasian lineage is considered to have broader range of hosts, such as pigs, horses, dogs, ferrets, seals and humans ().
Figure 8
In wild waterfowl, the detection rate of H3-subtype AIV is very high. Avian influenza virus can also spread across continents through wildfowl migration. H3N2 Hong Kong influenza virus recombined with human influenza H2N2 polygenes in 1968, which caused the Hong Kong human influenza pandemic, and the HA of H3N2 AIV deviated from that of the avian-origin AIV. Therefore, the antigenicity of contemporary human H3 influenza virus is significantly different from that of H3 AIV (). H3-subtype AIV was introduced into horses in the 1960s, and its HA antigenicity has changed since then, gradually leading to the formation of a separate lineage (). In 2006, H3N2 AIV entered the canine population and formed a lineage of canine influenza virus. The haemagglutinin of all porcine H3 viruses are derived from those of human viruses. Therefore, this lineage is in the same lineage as human influenza virus in the evolutionary tree. Notably, in 2022, there were three cases of human infection with avian-derived H3N8 influenza virus in China. We downloaded their HA protein-encoding gene sequences from the NCBI, which were A/Changsha/1000/2022, A/China/CSKFQ-22-5/2022 and A/Henan/4-10CNIC/2022. After alignment and pairwise comparison with other H3-subtype AIV sequences, the HA of human H3N8 strain A/Henan/4-10CNIC/2022 and chicken H3N8 strain A/chicken/Henan/F0308/2022 had the highest homology, indicating that the new H3N8 virus causing human infection was derived from chickens (). The above studies show that H3-subtype AIV still has the risk of causing a pandemic in the human population.
4 Characteristics of the viral genome
4.1 Selection analysis
The ratio of nonsynonymous substitutions to synonymous substitutions (dN/dS) is commonly used to quantify the magnitude of evolutionary selection pressure on protein-coding genes. A higher dN/dS ratio reflects the potential influence of positive selection on genes during evolution, contributing to adaptation to environmental changes or the acquisition of new functions. In this study, H3NX AIV sequences were aligned and screened using MEGA 11.0 software. The dN/dS ratio was evaluated for each segment of the H3NX AIV using Launch DnaSP6 software. Specifically, all sequences were selected without annexed bases and had complete coding regions. The analysis that indicated that the NS, NA-N2, HA, and M2protein gene segments may have experienced higher selection pressure than the others (Figure 9; Table 1), which exhibited higher dN/dS substitution ratios.
Figure 9
Table 1
| Mean dN/dS | dN | dS | dN/dS |
|---|---|---|---|
| HA | 0.06379 | 0.4966 | 0.128453 |
| NA-N2 | 0.05904 | 0.36369 | 0.162336 |
| NA-N6 | 0.04017 | 0.47573 | 0.084439 |
| NA-N8 | 0.05026 | 0.48927 | 0.102724 |
| M1 | 0.01635 | 0.2705 | 0.060444 |
| M2 | 0.03018 | 0.21376 | 0.141186 |
| NP | 0.02075 | 0.48022 | 0.043209 |
| NS | 0.08151 | 0.45208 | 0.1803 |
| PA | 0.01253 | 0.42086 | 0.29772 |
| PB1 | 0.01242 | 0.43912 | 0.028284 |
| PB2 | 0.01277 | 0.42527 | 0.030028 |
The result of the dN/dS calculation.
4.2 Three-dimensional structure of H3-subtype AIV HA protein
Studies have shown that mutations in the HA protein receptor binding domains Q226L and G228S will change the binding of viral receptors so that they can bind not only to α-2,3-linked SA but also to α-2,6-linked SA (). Then, human infection with avian influenza may be possible. In addition, the substitution of R62I, N92, A144G and N145S in H3-subtype AIV HA protein may also increase the binding ability of the virus to human receptors ().
Here, the three-dimensional structure of the H3-subtype AIV HA protein was built by PyMOL software. A/chicken/Hong Kong/37/1978 (H3N2) and A/Hong Kong/1/1968 (H3N2) were selected for structural prediction. The structure of H3-subtype AIV HA protein was built through homology modeling, and suitable templates were selected using Alphafold2 (Figure 10). Only the monomeric structure of HA is displayed in the image, with key amino acid residues that affect viral biological characteristics labelled.
Figure 10
5 Prevention and control of H3-subtype AIV
The transmission of H3-subtype avian influenza virus from wild birds to poultry is characterized by unpredictability and uncontrollability. Therefore, at this stage, vaccination remains the best measure to prevent and control outbreaks of H3-subtype avian influenza. However, current research on AIV vaccines is mostly focused on the H5, H7, and H9 subtypes, with a lack of vaccines specifically targeting H3-subtype avian influenza on the market. Nonetheless, H3-subtype influenza virus-like particle vaccine (; ; ), epitope hemagglutinin vaccine (; ), and mucosal vaccine () have made some progress in humans and pigs, which could serve as a foundation for the future development of safer, broader spectrum, and more immunoprotective H3-subtype avian influenza virus vaccine.
Additionally, H3-subtype AIV, as a LPAIV, is more easily overlooked. Treatment after illness is not worthwhile. Isolating the source of infection is an effective measure for avoiding H3-subtype AIV infection in poultry. Therefore, it is particularly important for the prevention and control of H3-subtype AIV to strengthen the regular census and monitoring of H3-subtype AIV in wild birds and poultry.
6 Conclusion
H3-subtype AIV is in a state of evolution and recombination. Frequent recombination occurred between different subtypes, and cross-species transmission occurred. Moreover, multiple mammalian adaptive mutation sites were found on H3-subtype AIV HA protein. These findings indicate that H3-subtype AIV is gradually adapting to mammals and even humans. Therefore, the monitoring of mutation and recombination in H3-subtype AIVs should be continued, and efficient vaccines should be developed to prevent and control the prevalence of H3-subtype AIV.
Statements
Author contributions
JY: Writing – original draft. QY: Writing – review & editing. JL: Data curation, Software, Writing – review & editing. YZ: Writing – review & editing. MH: Writing – review & editing. YG: Funding acquisition, Project administration, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Natural Resource Affairs (Ecological Forestry Construction) Project of the Guangdong Forestry Department (grant number K23051), the Innovation and Strengthening Project of Guangdong Ocean University (grant number 230419067), and a Ph.D. start-up grant (grant number 521202292).
Acknowledgments
We thank the researchers and labs that submitted sequences of AIVs to the GISAID and NCBI databases.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Summary
Keywords
avian influenza virus, H3-subtype, genetics, evolution, interspecies transmission
Citation
Yu J, Yao Q, Liu J, Zhou Y, Huo M and Ge Y (2023) Concern regarding H3-subtype avian influenza virus. Front. Microbiol. 14:1327470. doi: 10.3389/fmicb.2023.1327470
Received
25 October 2023
Accepted
15 November 2023
Published
07 December 2023
Volume
14 - 2023
Edited by
Peirong Jiao, South China Agricultural University, China
Reviewed by
Huapeng Feng, Zhejiang Sci-Tech University, China; Xin Yin, Chinese Academy of Agricultural Sciences (CAAS), China
Updates
Copyright
© 2023 Yu, Yao, Liu, Zhou, Huo and Ge.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ye Ge, geye_perfect@126.com
†These authors share first authorship
Disclaimer
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