Abstract
Since the emergence of human H3N2 influenza A viruses in the pandemic of 1968, these viruses have become established as strains of moderate severity. A decline in virulence has been accompanied by glycan accumulation on the hemagglutinin globular head, and hemagglutinin receptor binding has changed from recognition of a broad spectrum of glycan receptors to a narrower spectrum. The relationship between increased glycosylation, binding changes, and reduction in H3N2 virulence is not clear. We evaluated the effect of hemagglutinin glycosylation on receptor binding and virulence of engineered H3N2 viruses. We demonstrate that low-binding virus is as virulent as higher binding counterparts, suggesting that H3N2 infection does not require either recognition of a wide variety of, or high avidity binding to, receptors. Among the few glycans recognized with low-binding virus, there were two structures that were bound by the vast majority of H3N2 viruses isolated between 1968 and 2012. We suggest that these two structures support physiologically relevant binding of H3N2 hemagglutinin and that this physiologically relevant binding has not changed since the 1968 pandemic. Therefore binding changes did not contribute to reduced severity of seasonal H3N2 viruses. This work will help direct the search for factors enhancing influenza virulence.
Highlights
To seven additional glycosylation sites on the HA globular head (Fig. 1)
Virus neutralization by lung-resident surfactant protein D (SP-D)[11], the respiratory tract collectin, and attenuation of H3N2 Influenza A viruses (IAVs) infection through ER stress pathways[12], has at least in part contributed to the observed effects
As indicated by two studies using hemadsorption[10] and sialyl glycoconjugate binding[22] assays, the progressive addition of glycans to specific sites decreased H3N2 IAV binding to its receptors, the precise SA receptors affected by additional glycosylation were not studied
Summary
To seven additional glycosylation sites on the HA globular head (Fig. 1). While some human isolates have lost some globular head glycans over this time[5], the general trend toward increasing glycosylation is clear. The stepwise increase in the number of N-linked glycosylation sites on the H3 globular head has been shown to reduce virulence of H3N2 strains[9,10,11]. Data from several studies suggested a link between declining morbidity and mortality associated with H3N2 infection in humans and reduced binding to SA-containing receptors[18,21,22]. In contrast to either conclusion, as well as to the suggestion of a link between reduced binding to SA-containing receptors and the declining morbidity or mortality associated with H3N2 infection in humans[18,21,22], binding data from a collection of human H3N2 IAVs that circulated from 1968 through 2012 did not indicate a correlation between the strength of receptor binding and virulence and ability to transmit in human population[13]. We propose that this disconnection is in part due to universal recognition of two specific sialylated structures
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