SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

Virology. 2020 Apr:543:43-53. doi: 10.1016/j.virol.2020.01.004. Epub 2020 Jan 7.

Abstract

Viruses possessing class I fusion proteins require proteolytic activation by host cell proteases to mediate fusion with the host cell membrane. The mammalian SPINT2 gene encodes a protease inhibitor that targets trypsin-like serine proteases. Here we show the protease inhibitor, SPINT2, restricts cleavage-activation efficiently for a range of influenza viruses and for human metapneumovirus (HMPV). SPINT2 treatment resulted in the cleavage and fusion inhibition of full-length influenza A/CA/04/09 (H1N1) HA, A/Aichi/68 (H3N2) HA, A/Shanghai/2/2013 (H7N9) HA and HMPV F when activated by trypsin, recombinant matriptase or KLK5. We also demonstrate that SPINT2 was able to reduce viral growth of influenza A/CA/04/09 H1N1 and A/X31 H3N2 in cell culture by inhibiting matriptase or TMPRSS2. Moreover, inhibition efficacy did not differ whether SPINT2 was added at the time of infection or 24 h post-infection. Our data suggest that the SPINT2 inhibitor has a strong potential to serve as a novel broad-spectrum antiviral.

Keywords: Antiviral therapy; HAI-2; HMPV; HMPV F; Hemagglutinin; Influenza; Proteases; SPINT2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Host-Pathogen Interactions
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Influenza A Virus, H1N1 Subtype / growth & development
  • Influenza A Virus, H1N1 Subtype / metabolism
  • Influenza A Virus, H1N1 Subtype / physiology
  • Influenza A Virus, H3N2 Subtype / drug effects
  • Influenza A Virus, H3N2 Subtype / growth & development
  • Influenza A Virus, H3N2 Subtype / metabolism
  • Influenza A Virus, H3N2 Subtype / physiology
  • Influenza A Virus, H7N9 Subtype / drug effects
  • Influenza A Virus, H7N9 Subtype / growth & development
  • Influenza A Virus, H7N9 Subtype / metabolism
  • Influenza A Virus, H7N9 Subtype / physiology
  • Influenza A virus / drug effects*
  • Influenza A virus / growth & development
  • Influenza A virus / metabolism
  • Influenza A virus / physiology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / pharmacology*
  • Metapneumovirus / drug effects*
  • Metapneumovirus / growth & development
  • Metapneumovirus / metabolism
  • Metapneumovirus / physiology
  • Peptide Hydrolases / metabolism
  • Protease Inhibitors / pharmacology
  • Recombinant Proteins / pharmacology
  • Serine Endopeptidases / metabolism
  • Serine Proteinase Inhibitors / metabolism
  • Serine Proteinase Inhibitors / pharmacology*
  • Trypsin Inhibitors / metabolism
  • Trypsin Inhibitors / pharmacology
  • Viral Fusion Proteins / metabolism*

Substances

  • Hemagglutinin Glycoproteins, Influenza Virus
  • Membrane Glycoproteins
  • Protease Inhibitors
  • Recombinant Proteins
  • SPINT2 protein, human
  • Serine Proteinase Inhibitors
  • Trypsin Inhibitors
  • Viral Fusion Proteins
  • Peptide Hydrolases
  • Serine Endopeptidases
  • TMPRSS2 protein, human