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Virus envelope tissue factor promotes infection in mice.

Michael R Sutherland1,2, Ayo Y Simon1,2,3,4, Iryna Shanina5

  • 1Canadian Blood Services, Center for Innovation, Vancouver, Canada.

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|January 20, 2019
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Tissue factor (TF) on herpes simplex virus 1 (HSV1) enhances infection. Targeting viral TF with anticoagulants or PAR2 agonists proved antiviral in mice, suggesting TF as a novel pan-specific antiviral target.

Keywords:
anticoagulantcoagulationprotease-activated receptortissue factorvirus infection

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Area of Science:

  • Virology and Immunology
  • Hemostasis and Thrombosis
  • Infectious Diseases

Background:

  • Tissue factor (TF) initiates coagulation and mediates cell signaling via protease-activated receptor 2 (PAR2).
  • Host cell-derived TF has been identified on viral envelopes, enhancing in vitro infection.
  • The in vivo role of viral TF and its interaction with PAR2 in herpes simplex virus type 1 (HSV1) infection remain to be elucidated.

Purpose of the Study:

  • To investigate the in vivo role of HSV1 surface TF in viral infection.
  • To evaluate TF as a potential antiviral therapeutic target.
  • To examine the modulatory role of PAR2 in HSV1 infection in vivo.

Main Methods:

  • Purified HSV1 with or without envelope TF was generated using a TF-inducible cell line.
  • Mice (BALB/c, C57BL/6J, and C57BL/6J PAR2 knockout) were intravenously inoculated with HSV1.
  • Viral load in organs (brain, lung, heart, spinal cord, liver) was quantified via plaque assays and qPCR 3 days post-inoculation.

Main Results:

  • HSV1 infection across all evaluated organs was dependent on viral TF.
  • Antiviral effects were observed with virus-specific anti-TF monoclonal antibodies and small-molecule coagulation inhibitors.
  • PAR2 knockout mice and PAR2 agonist peptide demonstrated that PAR2 modulates HSV1 infection in vivo.

Conclusions:

  • TF on the HSV1 envelope is essential for systemic infection in mice.
  • Targeting viral TF with anticoagulants or TF-specific inhibitors represents a promising pan-specific antiviral strategy.
  • PAR2 plays a significant role in modulating HSV1 pathogenesis, indicating its potential as a therapeutic target.