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

Marco R. Straus, Jonathan T. Kinder, Michal Segall, Rebecca Ellis Dutch, Gary R. Whittaker

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)43-53
Number of pages11
JournalVirology
Volume543
DOIs
StatePublished - Apr 2020

Bibliographical note

Funding Information:
J.T.K. and R.E.D. thank Dr. John Williams from University of Pittsburgh Children's Hospital for kindly providing the 54G10 anti-HMPV F antibody. This work was funded by National Institutes of Health grant 5R21AI117300.

Funding Information:
J.T.K. and R.E.D. thank Dr. John Williams from University of Pittsburgh Children's Hospital for kindly providing the 54G10 anti-HMPV F antibody. This work was funded by National Institutes of Health grant 5R21AI117300 .

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Antiviral therapy
  • HAI-2
  • HMPV
  • HMPV F
  • Hemagglutinin
  • Influenza
  • Proteases
  • SPINT2

ASJC Scopus subject areas

  • Virology

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