Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium

Pathog Dis. 2013 Nov;69(2):87-100. doi: 10.1111/2049-632X.12053. Epub 2013 Jul 2.


Influenza is an acute infection of the respiratory tract, which affects each year millions of people. Influenza virus infection is initiated by the surface glycoprotein hemagglutinin (HA) through receptor binding and fusion of viral and endosomal membranes. HA is synthesized as a precursor protein and requires cleavage by host cell proteases to gain its fusion capacity. Although cleavage of HA is crucial for virus infectivity, little was known about relevant proteases in the human airways for a long time. Recent progress in the identification and characterization of HA-activating host cell proteases has been considerable however and supports the idea of targeting HA cleavage as a novel approach for influenza treatment. Interestingly, certain bacteria have been demonstrated to support HA activation either by secreting proteases that cleave HA or due to activation of cellular proteases and thereby may contribute to virus spread and enhanced pathogenicity. In this review, we give an overview on activation of influenza viruses by proteases from host cells and bacteria with the main focus on recent progress on HA cleavage by proteases HAT and TMPRSS2 in the human airway epithelium. In addition, we outline investigations of HA-activating proteases as potential drug targets for influenza treatment.

Keywords: HAT; TMPRSS2; influenza treatment by protease inhibitors; influenza virus hemagglutinin; proteolytic cleavage; viral-bacterial pneumonia.

Publication types

  • Review

MeSH terms

  • Animals
  • Bacteria / enzymology*
  • Bacteria / metabolism
  • Epithelium / enzymology*
  • Epithelium / metabolism
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism*
  • Host-Pathogen Interactions*
  • Humans
  • Orthomyxoviridae / physiology*
  • Peptide Hydrolases / metabolism*
  • Virus Internalization*


  • Hemagglutinin Glycoproteins, Influenza Virus
  • Peptide Hydrolases