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Host switching #mutations in #H5N1 #influenza hemagglutinin suppress site-specific activation dynamics

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By G.M.

 


Abstract

Increase in human H5N1 spillover infections resulting from dissemination of highly pathogenic avian influenza (HPAI) virus into bird and mammal populations raises concerns about HPAI gaining human transmissibility. Studies identified hemagglutinin (HA) acid stability and receptor preference as essential traits that shape host tropism. Mutations that increase HA stability and affinity for α−2,6-linked sialic acids have been shown to confer airborne transmissibility in a ferret model, however mechanisms of activation of H5 subtype HA are poorly understood and the effect of adaptive mutations on HA function has been largely inferred from static structures. Here, we use hydrogen/deuterium-exchange mass spectrometry to dissect activation dynamics for two ancestral H5 HPAI HA, their transmission-adapted HA, and a contemporary HA. We identify variation in receptor binding site flexibility and demonstrate that adaptive mutations result in suppression of fusion peptide dynamics and stabilization of a key interface involved in activation. The contemporary H5 isolated from a spillover event exhibits a relatively protected fusion peptide and moderately depressed activation pH compared to ancestral HAs. Our studies of activation dynamics in H5 together with analysis of H1 and H3 HAs reveal subtype-specific patterns that correlate with mutation sites and indicate underlying physical constraints on influenza HA adaptation.

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Link: https://www.nature.com/articles/s41467-025-66926-y

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