Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Eur J Cell Biol. Jul-Sep 2015;94(7-9):375-83. doi: 10.1016/j.ejcb.2015.05.013. Epub 2015 Jun 1.

Abstract

Cellular proteases are reponsible for activation of influenza virus hemagglutinin (HA) in epithelial tissues of the respiratory tract. The trans-Golgi network (TGN) is the main subcellular compartment where HA cleavage occurs during its biosynthesis. The proteolytic HA cleavage is an indispensable prerequisite for the fusion of viral with endosomal membrane and the delivery of the virus genome into the cell. Both, the structure and accessibility of the HA cleavage site determine the responsible host protease(s) for cutting. Most influenza virus strains contain a HA sequence with a single arginine at the cleavage site suitable for processing by the trypsin-like serine proteases human airway trypsin-like protease (HAT) and transmembrane protease serine 2 (TMPRSS2), albeit a minority of viruses possesses HA cleavage site motifs that are processed by other proteases. TMPRSS2-deficient mice demonstrated the relevance of TMPRSS2 for pneumotropism and pathogenicity of H1N1 and H7N9 virus infections. In contrast, H3N2 virus infections are promoted by an additional not yet identified protease. Highly pathogenic avian H5 and H7 viruses are characterized by an enlarged cleavage site loop containing a multibasic amino acid motif, where the eukaryotic subtilases furin or PC5/6 cleave. Their ubiquitous presence in the organism allows a systemic virus infection. Peptidomimetic inhibitors derived from the HA cleavage site inhibit the HA-activating proteases and thus virus propagation.

Keywords: Cellular host proteases; Compartimentalization of proteases; Protease inhibitors as antivirals; Proteolytic activation of influenza viruses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Furin / metabolism
  • Hemagglutinin Glycoproteins, Influenza Virus / biosynthesis
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism*
  • Humans
  • Influenza A Virus, H1N1 Subtype / pathogenicity*
  • Influenza A Virus, H3N2 Subtype / pathogenicity
  • Influenza A Virus, H7N9 Subtype / pathogenicity*
  • Influenza, Human / pathology
  • Influenza, Human / virology
  • Mice
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Proprotein Convertase 5 / metabolism
  • Respiratory Mucosa / virology
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism*
  • Serine Proteases / metabolism*
  • trans-Golgi Network / metabolism

Substances

  • Hemagglutinin Glycoproteins, Influenza Virus
  • Serine Proteases
  • Proprotein Convertase 5
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • TMPRSS2 protein, mouse
  • human airway trypsin-like protease
  • Furin