Haemagglutinin | Viral envelope | Attachment to sialic acid residues on airway and alveolar epithelium, membrane fusion and viral entry | Alternate binding to α-2,3 or -2,6 linked sialic acid contributes to pathogenicity In the human airway, proteolytic cleavage and disease severity is connected to host proteases TMPRSS2 and HAT [25–27] The addition of N-linked glycosylations mask haemagglutinin as an antigenic epitope [28–31] but trigger recognition by C-type lectins [32–34] | DAS181 (cleavage of sialic acids), flufirvitide (peptide inhibitor binding to haemagglutinin) |
Neuraminadase | Viral envelope | Enzymatic cleavage of terminal sialic acid residues from newly formed virions and release of progeny | After haemagglutinin, neuraminadase is the major antigenic epitope Currently approved therapies for IAV infection (osteltamivir, zanamivir, laninamivir and peramivir) target neuraminadase | |
Matrix protein-2 | Viral envelope | Proton selective ion channel required for viral entry, assembly and budding | Matrix protein-2 has been suggested to promote apoptosis by inhibition of autophagy [35] and induces degradation of ENaC and CFTR [36, 37] and, therefore, impacts alveolar fluid clearance | AVI-7100 (interference with M segment gene expression) |
Matrix protein-1 | Viral matrix | Structural links between the membrane and ribonucleoprotein core | | |
Polymerase proteins: PB1, PB2 and PA | Ribonucleoprotein core | RNA polymerase complex proteins | The polymerase subunits have been connected to viral pathogenicity and interact with >300 cellular proteins [38] Mutations can alter replication efficiency; e.g. a single amino acid substitution (E627K) induces higher pathogenicity in the 1918, 1957 and 1968 pandemic IAV strains [39, 40] and is found in circulating H5N1 and H7N9 variants | Favipiravir (nucleoside inhibitor targeting PB1) |
Nucleocapsid protein | Ribonucleoprotein core | Packaging of the viral genome | | |
Nonstructural protein-1 | Expressed during replication, not part of the mature virion | Immune evasion | Critical for viral evasion of the host immune response It binds a complex of viral RNA, RIG-1 and TRIM25 to inhibit downstream antiviral signalling [41, 42] It also induces the downregulation of the IFN-α receptor [43] and upregulates inhibitors of JAK/STAT signalling (SOCS1 and SOCS3) [43, 44] During infection, non-structural protein-1 also blocks pro-apoptotic signalling by protein kinase R [45, 46] and prevents the activation of NF-κB [47] | |
Nonstructural protein-2 | Expressed during replication, not part of the mature virion | Export of viral ribonucleoproteins
from the nucleus during viral replication | | |
PB1-F2# | Expressed during replication | Induction of host cell apoptosis | PB1-F2 increases mitochondrial membrane permeability through interactions with mitochondrial membrane proteins ANT3 and VDAC, to enhance BAK/BAX-mediated cytochrome C release [48–50] | |