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 viruses cause respiratory infections by targeting the epithelial cells lining the respiratory tract. These surfaces are covered by a mucous layer composed of a variety of small solutes and glycoproteins derived among others from goblet cells [67] . This semi-fluid layer in turn conditions the underlying cells and determines their physiological state, including the activities of their uptake and secretion pathways. It will be important to determine to what extent the DYNA-DEP and DYNA-IND IAV entry pathways are operational under the conditions prevailing along the respiratory tract. Current knowledge on the protein composition of the fluids covering the respiratory epithelium is rapidly expanding by the application of proteomic methods to determine the protein composition of bronchial alveolar lavage fluids (BALF). These studies have extended the previous notion that BALF is highly similar in composition to serum. For example, just as for the serum proteome more than 85% of the total protein mass of the BALF proteome is accounted for by albumin, immunoglobulins, transferring, a1-antitrypsin and haptoglobin. In addition, many other proteins have been identified both in serum and in BALF including growth factors that can bind to growth factor receptor tyrosine kinases [68] [69] [70] . Thus, BALF is likely to harbor, just as serum, the protein factors that can activate signaling pathways that are crucial for the induction of DYNA-IND entry of IAV. In agreement herewith, macropinocytosis has been described as a functional entry pathway of Haemophilus influenzae into primary human bronchial epithelial cells [71] although the factors involved in signaling the process have not been identified yet.