Abstract
In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human-infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs. Our results revealed that in the presence of HA1 Q226, the triad of HA1 S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA1 226 of H2 and H3 HAs when binding to human-like receptors. Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.
Highlights
Recent years have witnessed an increasing number of human infections by avian influenza viruses including A(H7N9) [1,2] and A(H10N8) [3] in 2013
We found that the HA protein from the human-infecting A/Taiwan/2/ 2013(H6N1) virus, TW H6 HA, already possesses slight preference for human receptors, may act as an intermediate towards a complete human adaptation
We analyzed 737 non-redundant H6 HA sequences between 2000~2014. We found that they are separated into two major phylogenetic groups: Group I (268 sequences) that is mainly composed of H6N2 and H6N6 viruses from Asia, and Group II (459 sequences) which mostly consists of H6N1 and H6N2 viruses from Asia and around the world (S1 Fig)
Summary
Recent years have witnessed an increasing number of human infections by avian influenza viruses including A(H7N9) [1,2] and A(H10N8) [3] in 2013. The threat is especially immense given that H6 viruses are the most commonly observed subtype in wild aquatic birds [7,8], they infect a broad range of host including mice, ferrets, pigs and humans [9,10,11,12], over 30% of the currently circulating H6 viruses recognized human receptors and some even transmitted efficiently in PLOS ONE | DOI:10.1371/journal.pone.0134576. HA molecules of influenza virus isolated from various hosts differ in their ability to recognize receptors in which the linkage between sialic acid (Neu5Ac) and galactose (Gal) of the carbohydrate chain is either α(2,3) or α(2,6). In order to support efficient airborne transmission among humans to cause influenza epidemics and pandemics, an avian virus has to develop the ability to bind to human-like α(2,6)-linked sialic acid receptors with a concomitant loss of affinity for avian-like α(2,3)-linked sialic acid receptors. One critical question in the filed is to understand what sequence and structural changes in HA will endorse an affinity switch from avian receptors to human receptors
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