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.

As detailed above, the DYNA-IND entry pathway of IAV shares many characteristics with the endocytic pathway macropinocytosis. This is corroborated by the observation that IAV particles and dextran colocalize in large vesicles in the presence of FCS. Several viruses have recently been reported to enter cells via macropinocytosis [12, 14] . Apart from common factors like the requirement for PAK1 activation, actin dynamics and independence of dynamin, virus specific details have been described [34, 35] (Table 1 ). In part these might be contributed to differences in experimental conditions (e.g. cell types tested) but diversity in the molecular mechanisms by which macropinocytosis can be induced and executed is likely to exist and to be exploited by viruses. Whereas vaccinia virus is able to trigger its own macropinocytic uptake [34, 43] , we have described a macropinocytosis pathway that is operational under conditions that are activated by components in serum. Still, this does not exclude signaling induced by virus-host cell interactions, which are for instance suggested by the significant increase of FITC-dextran uptake in the presence of IAV. The possible requirement for costimulatory signals from serum components and virus imposes an additional layer of complexity on the analysis of IAV entry via DYNA-IND pathways.