Use this URL to cite or link to this record in EThOS:
Title: Characterization of receptor binding of H10N7 seal viruses
Author: Zhang, Jie
ISNI:       0000 0004 7970 0295
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Restricted access.
Access from Institution:
Influenza pandemics are caused by influenza A viruses. Wild waterfowl is the natural reservoir of most influenza A viruses as all 16 subtypes are found in wild birds. Variations in the receptor binding site of hemagglutinin (HA), one of the two major surface proteins of influenza A viruses, alter virus receptor binding properties and allow virus adaptation to different species. The Gln226Leu substitution in the receptor binding site appears to play a particularly important role in switching the binding preference of viruses of the H2, H3, H5, and H7 subtypes from avian to human receptor. The change facilitates the adaptation of these viruses in humans. The first reported case of human infection by an avian H10N8 viruses occurred in Jiangxi province in 2013. Sequence analysis showed that residue 226 in the receptor binding site, from this avian-origin H10N8 virus, is Gln. Binding studies suggested that the virus has strong binding to both avian and human receptor. The influence of substitutions at residue 226 on the receptor binding properties of H10 subtype viruses was unknown because of the lack of naturally occurring substitutions. H10N7 influenza virus infection of seals caused many deaths along the eastern shore of the North Sea in 2014. Variants such as Gln226Leu, Gln226Leu/Gly228Ser and Gln226Leu/del228 were identified from deep sequencing analysis of samples isolated in this outbreak. In order to understand the influence of these variations on the biology of the virus I investigated their receptor binding properties using bio-layer interferometry (BLI). Further insights were gained by using X-ray crystallography to determine the three dimensional structures of these HAs in complex with both human and avian receptor analogues. Based on the BLI results and structure analysis, I conclude that the Gln226Leu substitution in the HA receptor binding site switches the binding preference of H10 seal viruses from avian to dual preference. Moreover, the human receptor, bound to H10 Germany seal Gln226Leu HA and to H10 Netherland seal 226Leu HA, adopts the 'folded back' conformation typical of the way human receptor binds to pandemic viruses. Thus, the Gln226Leu substitution changes the binding avidity and binding mode of H10 seal viruses such that they gain the features of pandemic viruses and are better adapted to propagation in mammals.
Supervisor: Malim, Michael Henry Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available