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

doi:10.1016/j.virol.2020.01.004

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 journal › Article › peer-review

19 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 language	English
Pages (from-to)	43-53
Number of pages	11
Journal	Virology
Volume	543
DOIs	https://doi.org/10.1016/j.virol.2020.01.004
State	Published - Apr 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

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. 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 .

Funders	Funder number
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases	R21AI117300
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh

Keywords

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

ASJC Scopus subject areas

Virology

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10.1016/j.virol.2020.01.004

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title = "SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses",

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",

author = "Straus, \{Marco R.\} and Kinder, \{Jonathan T.\} and Michal Segall and Dutch, \{Rebecca Ellis\} and Whittaker, \{Gary R.\}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = apr,

doi = "10.1016/j.virol.2020.01.004",

language = "English",

volume = "543",

pages = "43--53",

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AU - Straus, Marco R.

AU - Kinder, Jonathan T.

AU - Segall, Michal

AU - Dutch, Rebecca Ellis

AU - Whittaker, Gary R.

PY - 2020/4

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N2 - 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.

AB - 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.

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KW - HMPV F

KW - Hemagglutinin

KW - Influenza

KW - Proteases

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VL - 543

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JO - Virology

JF - Virology

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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