The role of fusion activity of influenza A viruses in their biological properties

Abstract

Summary. -Infl uenza A viruses (IAVs) cause acute respiratory infections of humans, which are repeated yearly. Human IAV infections are associated with signifi cant morbidity and mortality and therefore they represent a serious health problem. All human IAV strains are originally derived from avian IAVs, which, aft er their adaptation to humans, can spread in the human population and cause pandemics with more or less severe course of the disease. Presently, however, the potential of avian IAV to infect humans and to cause the disease cannot be predicted. Many studies are therefore focused on factors infl uencing the virulence and pathogenicity of IAV viruses in a given host. Th e virus-host interaction starts by virus attachment via the envelope glycoprotein hemagglutinin (HA) to the receptors on the cell surface. In addition to receptor binding, HA mediates also the fusion of viral and endosomal membranes, which follows the virus endocytosis. Th e fusion potential of HA trimer, primed by proteolytic cleavage, is activated by low pH in endosomes, resulting in HA refolding into the fusion-active form. Th e HA conformation change is predetermined by its 3-D structure, is pH-dependent, irreversible and strain-specifi c. Th e process of fusion activation of IAV hemagglutinin is crucial for virus entry into the cell and for the ability of the virus to replicate in the host. Here we discuss the known data about the characteristics of fusion activation of HA in relation to IAV virulence and pathogenicity.Keywords: infl uenza A viruses; pH optimum of fusion; IAV virulence and pathogenicity; HA conformation change; IAV interspecies transmission; adaptation changes * Corresponding author. E-mail: viruevar@savba.sk; phone: 421-2-59302427. Abbreviations: HA = hemagglutinin; HA0 = HA precursor; HA1 = heavy chain of HA; HA2 = light chain of HA; HPAI = highly pathogenic avian infl uenza; IAV(s) = infl uenza A virus(es); LPAI = low pathogenic avian infl uenza; M1 protein = matrix protein; mRNA = messenger RNA; NA = neuraminidase; NEP protein = nuclear export protein; NS1 protein = nonstructural protein 1; PA = polymerase acidic protein; PB1 = polymerase basic protein 1; PB2 = polymerase basic protein 2; RBS = receptor binding site; RNA = ribonucleic acid; RNP = ribonucleoprotein; SA = sialic acid; vRNA = viral RNA Content: 1. Introduction 2. Structure and function of hemagglutinin 2.1 Receptor binding activity and IAV host tropism 2.2 Fusion activity and structural rearrangements of HA during the membrane fusion 3. Th e HA cleavability by host proteases and HA fusion activation pH as factors of IAV virulence and pathogenicity 3.1 Cleavage activation of HA as a determinant of IAV pathogenicity 3.2 Fusion activation pH as a determinant of IAV virulence 4. Th e role of fusion activation pH and stability of HA in the adaptation of IAV to the new host 5. Other viral proteins infl uencing the IAV virulence 6. Conclusion

Structural Basis of SARS-CoV-2– and SARS-CoV–Receptor Binding and Small-Molecule Blockers as Potential Therapeutics

“…Following hACE receptor binding and endocytosis, acidification of the internalized endosome is required to retrieve the internalized cargo proteins and viral RNAs that support coronavirus replication (53)(54)(55)(56). Lysosomal cathepsins are essential for SARS-CoV-2, SARS-CoV, and MERS-CoV entry via endocytosis (10).…”

Biological properties of influenza A virus mutants with amino acid substitutions in the HA2 glycoprotein of the HA1/HA2 interaction region

“…It was shown that the HA conformation is influenced by ionizable amino acids in several important regions of the HA trimer, including the fusion peptide, the coiled-coil region of the light chain of HA, and the area of interaction between the HA1 and HA2 subunits [4,32]. At low pH, the region of amino acids 56-75 of HA2 gp undergoes the transition from loop to helix, which is an essential step for exposure of the N terminus of HA2 out from the HA trimer needed for its insertion into the target membrane [3,8,33,34]. The pH required for HA refolding and fusion activation varies among different strains and is closely related to the pH optimum of fusion and subsequently influences the replication ability of the virus.…”

“…Consequently, HA2 gp that in native conformation is covered by the HA1 globular part is exposed and its N terminus is inserted into the endosomal membrane. Finally, the fusion pore is formed, enabling the release of viral genome into the cytoplasm and its transport to the site of vRNA replication [ 8 ]. Although many studies have described the mechanism of IAV and endosomal membrane fusion, the details of this process are not yet clear [ 9, 10 ].…”

Development and Effects of Influenza Antiviral Drugs

“…In addition to binding to host cells, the second major function of HA is to mediate viral and cell membrane fusion [30,31]. This fusion process is essential for the introduction of the viral genome into cells [32][33][34]. Indeed, new antiviral drugs have been developed using HA as an antiviral target [35].…”