Thesis defense Mengying Liu

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Influenza A virus (IAV) infection of cells requires binding to cell surface receptors belonging to a diverse group of sugars called sialoglycans (Sias). According to a longstanding paradigm, IAVs infecting birds use different Sias (i.e. 2-3Sias) than human IAVs (using 2-6Sias), even though both types occur in both hosts. Adaptation to 2-6Sia binding specificity has been key to the generation of the 4 flu pandemics that occurred in a century. We developed novel techniques for dissecting the cell surface-displayed Sia repertoire for a more detailed identification of the role of individual Sia receptors and largely nuanced the paradigm of the strict dichotomy into “avian-type 2-3Sia” “human-type 2-6Sia” receptors. Tight cell surface binding by multiple simultaneous virus-Sia receptors only required few strong interactions (e.g. of a human IAV with 2-6Sia) when assisted by multiple (heteromultivalent) weak interactions (e.g. with 2-3Sia). In concordance, the development of binding strength of 2-3Sias and 2-6Sias with human H3N2 strains only gradually evolved over 10 years after the 1968 pandemic to high “human-type” receptor specificity which was reversed again after 1995. Genetically dissecting the surface-displayed Sia repertoire of HEK293 cells generated a cell-based glycan array for directing screening of the receptor requirements for infection and use of specific endocytic entry pathways. Our results demonstrate that many individual Sias of the diverse repertoire displayed on cells can contribute to IAV infection, likely by heteromultivalent interactions. Such a promiscuity in receptor requirements will expand the evolutionary options available for adaptation of IAVs to a new host.