A comprehensive comparison of the fifth‐wave highly pathogenic and low‐pathogenic H7N9 avian influenza viruses reveals potential threat posed by both types of viruses in mammals

Abstract

Before 2013, zoonotic influenza infections were dominated by H5N1 viruses in China. However, the emergence of the H7N9 viruses in early 2013 changed this dominance greatly, and more than 1,600 laboratory-confirmed human cases of H7N9 infections have been reported since then. To understand the underlying mechanism of the emergence of the fifth epidemic wave that shows an unexpected sharp increase, we systematically investigated the biological characteristics of the highly pathogenic (HP) and low-pathogenic (LP) H7N9 AIVs during this period. We first systematically analysed the haemagglutination assay gene of all the isolates available from the website and found that the HP and LP viruses differed a little in the well-established receptor binding sites and in other potentially important sites. Phylogenetic analysis showed that both the HP and LP viruses belong to the branch of the Yangtze River Delta, whereas they diverged to different small branches. To further compare the biological variations in the HP and LP viruses, we selected six HP and six LP strains for in-depth analysis, including receptor binding characteristics, thermal stability, viral replication and virulence in mice. The three major findings of this study were as follows: (a) Other potential site/sites may affect the receptor binding property of the H7N9 viruses; (b) the HP viruses displayed a higher thermostability than did the LP viruses, quite consistent with the epidemiological data during the summer period; and (c) one-third of the HP viruses were moderately pathogenic in mice, whereas all the LP viruses were nonpathogenic in this animal model. However, the LP viruses replicated more efficiently in the mouse lung and can spread to the extrarespiratory organs (spleen, kidney and brain). Taken together, our results suggest that both the HP and LP H7N9 viruses can pose a potential threat to public health, highlighting the importance of the continual surveillance of the H7N9 AIVs.

H7N9 Influenza Virus in China

“…Moreover, the T271A and Q591K mutations in PB2 have also occasionally been identified in highly pathogenic H7N9 viruses (Yang et al 2017). Mutations in other components of the viral RNP complex, including PB1 I368V and PA K356R, which were established in the H7N9 avian viruses (He et al 2018), as well as V100A, A404S, and S409N in PA, and V33I and I109V in NP, which were rarely observed in the highly pathogenic H7N9 human viruses (Chen et al 2016;Yang et al 2017), could also potentially contribute to the adaptation of H7N9 viruses in humans. Of note, mammalian-adaptive mutations were also acquired during virus replication in other mammals, such as PB2 T271A, E627K, and D701N in pigs (Liu et al 2014b).…”

“…Of note, in comparison to most of the H7N9 LPAIVs that contain 226L, the majority of the H7N9 HPAIVs possess 226Q (Yang et al 2017). However, the H7N9 HPAIVs maintained the dual receptor-binding affinity (He et al 2018), indicating the G186V mutation alone is capable of increasing the human-type receptorbinding affinity. In addition, a T160A mutation in HA was acquired by the H7N9 viruses (Gao et al 2013;Huang et al 2017), leading to the loss of an N-glycosylation site.…”

Avian influenza overview May – August 2018

“…None of the LPAIV induced mortality in mice, but the viruses caused weight loss and replicated efficiently in the lungs and spread to non-respiratory organs (brain, kidney and spleen). One third of the tested HPAIV A(H7N9) strains caused weight loss and death in infected mice (He et al, 2018). He et al (2018) compared six highly pathogenic A(H7N9) and six low pathogenic A(H7N9) viruses recovered from chickens in China in 2017 and found no differences in terms of molecular markers associated with the HA receptor binding capacity, but showed higher thermal stability of HP isolates (a possible factor contributing to better transmissibility of some HP viruses in ferrets).…”

“…One third of the tested HPAIV A(H7N9) strains caused weight loss and death in infected mice (He et al, 2018). He et al (2018) compared six highly pathogenic A(H7N9) and six low pathogenic A(H7N9) viruses recovered from chickens in China in 2017 and found no differences in terms of molecular markers associated with the HA receptor binding capacity, but showed higher thermal stability of HP isolates (a possible factor contributing to better transmissibility of some HP viruses in ferrets). Phylogenetic analyses proved that the isolates belong to the 'Yangtze Delta River' clade, but were placed in two separate branches consistent with the pathotype.…”

“…Since February 2013 a total of 1 567 human cases have been reported from outside of Europe, including 569 with fatal outcome (CHP, 2018; WHO, 2018c, online-a); see Figure 12 and Table 5). According to the Chinese National Influenza Center ( The virological characteristics of the HPAI and LPAI A(H7N9) viruses of the fifth wave were investigated and a higher thermostability as well as a slightly higher pathogenicity in mice of HPAI virus compared to LPAI virus were identified (He et al, 2018). Genetic changes of molecular markers in LPAI but also in HPAI viruses within the HA gene were described to possibly affect receptor binding properties.…”