Knockin’ on Cell’s Door: Influenza A Virus Adsorption and Its Pharmacological Inhibition

Abstract

Influenza A virus (IAV) is a widespread human respiratory pathogen that contributes significantly to morbidity and mortality worldwide. The adsorption of the virus into the cell surface is the earliest stage of its replication cycle. The key role of N-linked sialic acids (SIAs) as receptors for binding to IAV’s hemagglutinin (HA) has long been acknowledged. The molecular specificity of this interaction is a key factor in host range, pathogenicity, and transmissibility of various IAV subtypes. Along with this, a number of recent studies have introduced significant complexity into the picture of IAV adsorption and revealed a multitude of new molecules on host cell surfaces to serve as receptors and/or co-receptors for IAV attachment. For successful internalization of the adsorbed virus, downstream signal transduction is necessary to activate effector endocytosis mechanisms. In recent years, our understanding of the sophistication and variability of signal transduction pathways in the virus attachment site has significantly expanded, with the help of research techniques like fluorescence imaging of individual viruses in real-time, dominant-negative mutants, siRNA knockdowns, protein kinase selective inhibitors, phosphoproteome profiling, and others. These approaches deepen our knowledge of the molecules involved in the early stages of the IAV life cycle and also serve as the basis for the development of new effective antiviral drugs. In our review, we analyze recent publications on the mechanisms of IAV adsorption, newly discovered receptors for virus attachment, and signal transmission in the site of the adsorbed virion. Besides this, we consider new data on the development of selective inhibitors as antiviral drugs aimed at both viral and cellular factors of IAV adsorption.