Human norovirus GII.4(MI001) P dimer binds fucosylated and sialylated carbohydrates

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Abstract

Human noroviruses (HuNoV), members of the family Caliciviridae, are the major cause of acute viral gastroenteritis worldwide. Successful infection is linked to the ability of the protruding (P) domain of the viral capsid to bind histo-blood group antigens (HBGA). Binding to gangliosides plays a major role for many nonhuman calici- and noroviruses. Increasing evidence points to a broader role of sialylated carbohydrates such as gangliosides in norovirus infection. Here, we compare HBGA and ganglioside binding of a GII.4 HuNoV variant (MI001), previously shown to be infectious in a HuNoV mouse model. Saturation transfer difference nuclear magnetic resonance spectroscopy, native mass spectrometry (MS) and surface plasmon resonance spectroscopy were used to characterize binding epitopes, affinities, stoichiometry and dynamics, focusing on 3′-sialyllactose, the GM3 ganglioside saccharide and B antigen. Binding was observed for 3′-sialyllactose and various HBGAs following a multistep binding process. Intrinsic affinities (Kd) of fucose, 3′-sialyllactose and B antigen were determined for the individual binding steps. Stronger affinities were observed for B antigen over 3′-sialyllactose and fucose, which bound in the mM range. Binding stoichiometry was analyzed by native MS showing the presence of four B antigens or two 3′-sialyllactose in the complex. Epitope mapping of 3′-sialyllactose revealed direct interaction of α2,3-linked sialic acid with the P domain. The ability of HuNoV to engage multiple carbohydrates emphasizes the multivalent nature of norovirus glycan-specificity. Our findings reveal direct binding of a GII.4 HuNoV P dimer to α2,3-linked sialic acid and support a broader role of ganglioside binding in norovirus infection.

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Wegener, H., Mallagaray, Á., Schöne, T., Peters, T., Lockhauserbäumer, J., Yan, H., … Taube, S. (2017). Human norovirus GII.4(MI001) P dimer binds fucosylated and sialylated carbohydrates. Glycobiology, 27(11), 1027–1037. https://doi.org/10.1093/glycob/cwx078

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