Influenza A Virus: Cellular Entry.

Abstract

The frequent emergence of pathogenic viruses with pandemic potential has posed a significant threat to human health and economy, despite enormous advances in our understanding of infection mechanisms and devising countermeasures through developing various prophylactic and therapeutic strategies. The recent coronavirus disease (COVID-19) pandemic has re-emphasised the importance of rigorous research on virus infection mechanisms and highlighted the need for our preparedness for potential pandemics. Although viruses cannot self-replicate, they tap into host cell factors and processes for their entry, propagation and dissemination. Upon entering thehost cells, viruses ingeniously utilise the innate biological functions of the host cell to replicate themselves and maintain their existencein the hosts. Influenza A virus (IAV), which has a negative-sense, single-stranded RNA as its genome, is no exception. IAVs are enveloped viruses with a lipid bilayer derived from the host cell membrane and have a surface covered with the spike glycoprotein haemagglutinin (HA) and neuraminidase (NA). Viral genome is surrounded by an M1 shell, forming a "capsid" in the virus particle. IAV particles use HA to recognise sialic acids on the cell surface of lung epithelial cells for their attachment. After attachment to the cell surface, IAV particles areendocytosed and sorted into the earlyendosomes. Subsequently, as the earlyendosomes matureinto late endosomes, the endosomal lumen becomes acidified, andthe low pH of the lateendosomes induces conformational reaggangements in theHA toinitiate fusion between the endosomal and viral membranes. Upon fusion, the viral capsid disintegrates and the viral ribonucleoprotein (vRNP) complexescontaining the viral genome are released into the cytosol. The process of viral capsid disintegration is called "uncoating". After successful uncoating, the vRNPs are imported into the nucleus byimportin α/β (IMP α/β), where viral replication and transcription take placeand thenew vRNPs are assembled. Recently, we have biochemically elucidated the molecular mechanisms of the processes ofviral capsid uncoating subsequent viral genome dissociation. In this chapter,we present the moleculardetails of the viraluncoating process.