IFITM3 Clusters on Virus Containing Endosomes and Lysosomes Early in the Influenza A Infection of Human Airway Epithelial Cells

Kummer, Susann; Avinoam, Ori; Kräusslich, Hans-Georg

IAV hijacks cellular import mechanisms to enter the host cell, thereby making use of multiple entry routes. The binding of IAV by the sialylated receptor [8, 9] is followed by clathrin-mediated endocytosis [10, 11] or micropinocytosis [12] . It is reported that IAV entry is cell-type dependent [13] and that subtypes with a filamentous particle shape preferentially enter host cells via macropinocytosis [14] . The trimeric surface glycoprotein hemagglutinin (HA) is a key factor for several steps during viral entry via endocytosis [15, 16] . Irrespective of the entry mechanism, IAV exploits the non-linear endosomal pathway with its multitude of branches and needs to pass different stages of the endocytic machinery, which is assembled and constantly renewed around the internalized virus particles [17] [18] [19] . Endosomal trafficking to the perinuclear region is crucial for pH-dependent membrane fusion [20] [21] [22] , followed by the release of the viral genome into the cytosol and nuclear import [23] . The IAV genome is composed of eight single RNA strands in a negative sense orientation [24] , and each segment is complexed with the nucleoprotein NP [15, 24] , forming ribonucleoparticles (RNPs; [25, 26] ). Viral genome replication, splicing and transcription then occur in the nucleus. IAV replication is strongly inhibited by type 1 interferons already at the early stage, with Mx1 being identified as a crucial interferon-induced host protein blocking IAV replication [27] .