††††††††††† Haemagglutinin is key to the infectivity of influenza A virus.† A surface fusion glycoprotein embedded in the envelope of the virus, haemagglutinin must first be cleaved by the hostís trypsin-like proteases for the virus to be infectious.† In fact, the infectivity and pathogenicity of the virus is largely determined by the hostís trypsin-like proteases.† The processing of haemagglutinin by these proteases takes place on the membranes of the hostís airway epithelial cells, where haemagglutinin glycoprotein (HA0) is cleaved to produce HA1 and HA2 peptides.† The newly exposed N-terminal of the HA2 fusion peptide then acts to fuse the viral envelope to the cellular membrane of the host cell.† Once the membranes have fused, the virusí genetic material, negative-stranded RNA, can invade and take control of the host cell.†
††††††††††† Both the type and distribution of trypsin-like proteases in the host, as well as the susceptibility of HA0 to these enzymes, determine the infectivity and pathogenicity of the influenza virus.† Several different trypsin-like proteases can act on haemagglutinin, where both the tissues in which they act (e.g. epithelial or neuronal cell) and the position of cleavage of HA will affect the infectivity of the virus.† For instance, proteases present in the brain can cause the infection to take root there (in addition to epithelial cells), while the position of cleavage by the protease can determine how well it binds to receptors on the host cell in order to infect it.† Trypsin-like proteases known to cleave HA0 include tryptase Clara, mini-plasmin, ectopic anionic trypsin, mast cell tryptase, tryptase TC30, and brain trypsin I, the latter being a possible candidate for the rare cases of encephalitis that are associated with certain strains of the virus.† Most strains of influenza A are pneumotropic, localising the infection to airway epithelial cells, but a few strains can multiply in both airway epithelial cells and in neuronal cells, causing life-threatening encephalitis, such as occurred in the devastating 1918 Spanish Influenza pandemic.†
††††††††††† Haemagglutinin itself also determines the pathogenicity of the virus, which varies from avirulent strains to lethal ones, providing a genetic mechanism for the variation in viral virulence (although other viral proteins affect virulence as well). The differences between strains are primarily determined by the amino acid sequence at the HA0 cleavage site, where the precise linkage of HA to host receptors determines species preference.† For example, a switch in receptor specificity from receptors containing sialic acids connected to galactose in a a2-3 linkage (avian receptors) to a a2-6 linkage (human receptors) is required for influenza A virus to cross the species barrier in adapting to a human host Ė this requires adaptation in the binding capacity of HA.
††††††††††† The second major surface glycoprotein found on the influenza A viral envelope is neuraminidase. †This protein promotes the release of progeny virus from the host cell during the final stages of viral replication.† In addition, there is increasing evidence that neuraminidase can promote virus entry into host cells during the initial stage of infection.†
††††††††††† In particular, when a variant of the 1918 Spanish Influenza pandemic strain H1N1 was analysed, the neuraminidase was found to directly bind plasminogen, sequestering the protease precursor to achieve a higher local concentration.† The active form of the protease, plasmin, could then cleave and activate haemagglutinin, thereby promoting the viral infection of host cells. †This unusual function of neuraminidase was found to have a molecular basis, involving the appearance of a C-terminal lysine and the absence of an oligosaccharide side chain at another position on the neuraminidase molecule.† Such changes allowed the virus to infect cells other than its usual targets, and showed a possible means of how the virus could become highly pathogenic in humans.
††††††††††† Therefore, the ability of influenza A virus to cross the species barrier to yield a human-adapted variant involves several mechanisms, including variation in host proteases, variations in viral haemagglutinin and neuraminidase, as well as variations in several other viral proteins, not to mention the complex interplay of environmental factors.