RNA structure interactions and ribonucleoprotein processes of the influenza A virus

Dawson, Wayne K; Lazniewski, Michal; Plewczynski, Dariusz

The IAV infection begins with the virus binding to the surface of an epithelial cell on recognizing the sialic acid glycans. The main sialic acid is N-acetylneuramic acid in mammals and birds [56] , typically followed by galactose. These molecules can be connected with an a2,6 bond, which is abundant on the surface of cells in the upper respiratory tract of humans, or with an a2,3 bond, which is found in the digestive tract in birds or in the lungs or bronchial tissue in humans. Although sialylated glycans in epithelial cells are studied mostly for their role in disease, the function of such glycans is diverse, interfacing with signaling proteins and various structural and modulatory roles [57, 58] , and in epithelial cells in general, defense against oxidative stress [59] and even nutrition [60, 61] . To defend against infections, epithelial cells secrete mucin (mucous) in the respiratory tract [27, 57, 62] . The major components of mucin are glycans terminated with sialic acid together with various antimicrobials compounds [62] . For the virions to traverse the thick mucosal layer covering the epithelial cells in the lungs, the NA-tetramers on the surface of the influenza A virion must cleave through the sialic acid within the mucous [27] . This allows the HA-trimers of the IAV to interact with the sialylated glycans on the apical cell surface [63] , an event known as virus adsorption. This event is followed by internalization of the virus and the fusion process, which takes advantage of the specific features of HA. Owing to the process of proteolytic cleavage of the HA0 precursor [64] , the HA protein is divided into two subunits HA1 and HA2. HA1 forms the globular head that binds to specific glycans on the epithelial cells. HA2 anchors the HA to the viral membrane and facilitates membrane fusion of the virus with the lipid bilayer of the endosomes, where the virus enters an endosome and the fusion peptide (from HA2) interacts with the lipid bilayer. As a result of lowering the pH in the endosome, the HA subunit adopts a low pH conformation [65] . The fusion process also depends on whether the virion is spherical or filamentous. Binding for the spherical virion triggers the internalization into an endosome, where acidification causes the HAtrimers to aggregate or cluster [26, [66] [67] [68] . Filamentous virions are, however, too large to fit into a clathrin-coated pit; therefore, they must enter the cell through a process known as macropinocytosis [44, [69] [70] [71] ; a pathway also used by the Ebola virus and SARS virus [8] .