The hemagglutinin: a determinant of pathogenicity

Curr Top Microbiol Immunol. 2014;385:3-34. doi: 10.1007/82_2014_384.


The hemagglutinin (HA) is a prime determinant of the pathogenicity of influenza A viruses. It initiates infection by binding to cell surface receptors and by inducing membrane fusion. The fusion capacity of HA depends on cleavage activation by host proteases, and it has long been known that highly pathogenic avian influenza viruses displaying a multibasic cleavage site differ in protease sensitivity from low pathogenic avian and mammalian influenza viruses with a monobasic cleavage site. Evidence is increasing that there are also variations in proteolytic activation among the viruses with a monobasic cleavage site, and several proteases have been identified recently that activate these viruses in a natural setting. Differences in protease sensitivity of HA and in tissue specificity of the enzymes are important determinants for virus tropism in the respiratory tract and for systemic spread of infection. Protease inhibitors that interfere with cleavage activation have the potential to be used for antiviral therapy and attenuated viruses have been generated by mutation of the cleavage site that can be used for the development of inactivated and live vaccines. It has long been known that human and avian influenza viruses differ in their specificity for sialic acid-containing cell receptors, and it is now clear that human tissues contain also receptors for avian viruses. Differences in receptor-binding specificity of seasonal and zoonotic viruses and differential expression of receptors for these viruses in the human respiratory tract account, at least partially, for the severity of disease. Receptor binding and fusion activation are modulated by HA glycosylation, and interaction of the glycans of HA with cellular lectins also affects virus infectivity. Interestingly, some of the mechanisms underlying pathogenicity are determinants of host range and transmissibility, as well.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Birds
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism*
  • Humans
  • Influenza A virus / genetics
  • Influenza A virus / metabolism*
  • Influenza A virus / pathogenicity*
  • Influenza in Birds / genetics
  • Influenza in Birds / metabolism
  • Influenza in Birds / virology*
  • Influenza, Human / genetics
  • Influenza, Human / metabolism
  • Influenza, Human / virology*
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology*
  • Receptors, Virus / genetics
  • Viral Tropism


  • Hemagglutinin Glycoproteins, Influenza Virus
  • Receptors, Virus