H9 Influenza Viruses: An Emerging Challenge

Abstract

Influenza A viruses (IAVs) of the H9 subtype are enzootic in Asia, the Middle East, and parts of North and Central Africa, where they cause significant economic losses to the poultry industry. Of note, some strains of H9N2 viruses have been linked to zoonotic episodes of mild respiratory diseases. Because of the threat posed by H9N2 viruses to poultry and human health, these viruses are considered of pandemic concern by the World Health Organization (WHO). H9N2 IAVs continue to diversify into multiple antigenically and phylogenetically distinct lineages that can further promote the emergence of strains with pandemic potential. Somewhat neglected compared with the H5 and H7 subtypes, there are numerous indicators that H9N2 viruses could be involved directly or indirectly in the emergence of the next influenza pandemic. The goal of this work is to discuss the state of knowledge on H9N2 IAVs and to provide an update on the contemporary global situation.

Figure 1.

World map and approximate lineage/clade circulation in which H9 subtype influenza A viruses (IAVs) have been reported. Please see main text for full description of lineages/clades. The H9N2 subtype combination is the most commonly found in nature. Dark gray corresponds to areas of the world where the presence or circulation of H9 IAVs is unknown.

Figure 2.

Global phylogenetic star tree (BEAUTi and BEAST v1.10.4) of H9 influenza A viruses (IAVs) based on the HA1 nucleotide sequence. H9 major lineages are color coded, respectively: h9.1—North American, teal; h9.1.2—South American, purple; h9.2—Y439, blue; h9.2.2—Korean, pink; h9.3—BJ94, green; h9.4.1—G1-Eastern, red; h9.4.2—G1-Western, orange.

Figure 3.

Temporal most recent common ancestor (TMRCA) phylogenetic analysis generated with BEAUTi and BEAST v1.10.4 under a strict molecular clock of 600 H9N2 influenza A viruses (IAVs) HA1 nucleotide sequences aligned in MUSCLE 3.8.425 (IRD and GISAID databases at August 2019). H9N2 clades are color coded, respectively: h9.1—North American, teal; h9.1.2—South American, purple; h9.2—Y439, blue; h9.2.2—Korean, pink; h9.3—BJ94, green; h9.4.1—G1-Eastern, red; h9.4.2—G1-Western, orange. Animal reservoir and countries with most common isolations for each lineage are shown.

Figure 4.

Relevant structural features of the hemagglutinin (HA) of the H9 subtype. Homotrimers of the HA crystal structure of A/swine/Hong Kong/9/1998 (Protein databank ID:1JSD) colored in PyMOL. Selected receptor-binding site (RBS) residues are colored in red. HA1 and HA2 portions are highlighted in gray and slate blue, respectively. (A) The full HA homotrimer is shown. (B,C) Details of the HA globular head. Shown are the antigenic site H9-A (magenta) and H9-B (yellow). Other antigenic residues without assigned site classification are shown in cyan. Potential glycosylation sites are colored in dark blue.