Continuous Reassortment of Clade 2.3.4.4 H5N6 Highly Pathogenetic Avian Influenza Viruses Demonstrating High Risk to Public Health

Abstract

Since it firstly emerged in China in 2013, clade 2.3.4.4 H5N6 highly pathogenic avian influenza viruses (HPAIVs) has rapidly replaced predominant H5N1 to become the dominant H5 subtype in China, especially in ducks. Not only endemic in China, it also crossed the geographical barrier and emerged in South Korea, Japan, and Europe. Here, we analyzed the genetic properties of the clade 2.3.4.4 H5N6 HPAIVs with full genome sequences available online together with our own isolates. Phylogenetic analysis showed that clade 2.3.4.4 H5N6 HPAIVs continuously reassorted with local H5, H6, and H7N9/H9N2. Species analysis reveals that aquatic poultry and migratory birds became the dominant hosts of H5N6. Adaption to aquatic poultry might help clade 2.3.4.4 H5N6 better adapt to migratory birds, thus enabling it to become endemic in China. Besides, migratory birds might help clade 2.3.4.4 H5N6 transmit all over the world. Clade 2.3.4.4 H5N6 HPAIVs also showed a preference for α2,6-SA receptors when compared to other avian origin influenza viruses. Experiments in vitro and in vivo revealed that clade 2.3.4.4 H5N6 HPAIVs exhibited high replication efficiency in both avian and mammal cells, and it also showed high pathogenicity in both mice and chickens, demonstrating high risk to public health. Considering all the factors together, adaption to aquatic poultry and migratory birds helps clade 2.3.4.4 H5N6 overcome the geographical isolation, and it has potential to be the next influenza pandemic in the world, making it worthy of our attention.

Assessing potential pathogenicity of novel highly pathogenic avian influenza (H5N6) viruses isolated from Mongolian wild duck feces using a mouse model

“…Recent years have seen the replacement of the H5N1 subtype with H5N6 and H5N8 HPAIVs from the clade 2.3.4.4 as the dominant subtypes in circulation [ 14 , 16 , 21 , 46 , 47 ]. Here, we collected two new H5N6 isolates from nearby sites (90 km away from each other) that demonstrate a high degree of nucleotide similarity.…”

Subclinical Infection and Transmission of Clade 2.3.4.4 H5N6 Highly Pathogenic Avian Influenza Virus in Mandarin Duck (Aix galericulata) and Domestic Pigeon (Columbia livia domestica)

“…Genotype C1 was first detected in wild birds in Korea; however, genotype C4 became predominant in wild birds and poultry during epidemics in Korea [14]. The clade 2.3.4.4 H5N6 HPAI viruses have caused outbreaks in poultry in China as a major subtype also causing human infection [22], but this strain has not been identified in Korea since 2017.…”

Genetic analysis and biological characteristics of novel clade 2.3.4.4 reassortment H5N6 avian influenza viruses from poultry in eastern China in 2016

“…A previous study showed that human-derived H5N6 AIVs were highly pathogenic in mice (Pan et al, 2018), and avian-derived H5N6 generally showed variable pathogenicity in mice (Li et al, 2020, Song et al, 2019, Sun et al, 2020. Additionally, it has been reported that the H5N6 AIVs isolated in 2015 had more efficient replication potential and pathogenicity in mice than the AIVs isolated in 2014 (Kang et al, 2018), which might be related to the continuous mutations of the HA gene and the continuous reassortment of the internal genes of the avian H5N6 virus (Sun et al, 2018).…”