Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway

de Vries, Erik; Tscherne, Donna M.; Wienholts, Marleen J.; Cobos-Jiménez, Viviana; Scholte, Florine; García-Sastre, Adolfo; Rottier, Peter J. M.; de Haan, Cornelis A. M.

Influenza A virus (IAV) is an enveloped, segmented negativestrand RNA virus infecting a wide variety of birds and mammals. As its first step in infection IAV attaches to host cells by the binding of its major surface protein, the hemagglutinin (HA), to sialic acids, which are omnipresent on the glycolipids and glycoproteins exposed on the surfaces of cells. Where the structural requirements for this interaction have been studied in great detail, much less is known about whether and how the attachment to specific sialylated receptors (e.g. to N-linked glycoproteins, Olinked glycoproteins or gangliosides or even to specific receptors within these groups) affects the subsequent endocytic steps. Obviously, knowledge about the repertoire of endocytic pathways that can successfully be used by IAV will increase our insights into cell and species tropism of IAV. In turn, this will contribute to our understanding of the requirements for the generation of novel viruses with pandemic potential that can arise by exchange of RNA segments between currently circulating human serotypes and an animal virus during occasional co-infection in a human or an animal host.