Virus envelope tissue factor promotes infection in mice
Author(s): ,
Michael R. Sutherland
Affiliations:
Canadian Blood Services, Center for Innovation, Vancouver, Canada. Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
,
Ayo Y. Simon
Affiliations:
Canadian Blood Services, Center for Innovation, Vancouver, Canada. Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. African Centre of Excellence on Neglected Tropical Diseases and Forensic Biotechnology and Veterinary Teaching Hospital, Ahmadu Bello University, Zaria, Nigeria. Preclinical Research and Development, Eme
,
Iryna Shanina
Affiliations:
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
,
Marc S. Horwitz
Affiliations:
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
,
Wolfram Ruf
Affiliations:
Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, USA. Center for Thrombosis and Hemostasis, University Medical Center, Mainz, Germany
Edward L. G. Pryzdial
Affiliations:
Canadian Blood Services, Center for Innovation, Vancouver, Canada. Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
Correspondence: Ed Pryzdial, University of British Columbia, Centre for Blood Research, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada|Tel.: +1 604 822 3823|E‐mail: ed.pryzdial@blood.ca
ISTH Academy. Pryzdial E. Mar 1, 2019; 273407
Ed Pryzdial
Ed Pryzdial
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Journal Abstract
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Background
Tissue factor (TF) is the essential cell surface initiator of coagulation, and mediates cell signaling through protease‐activated receptor (PAR) 2. Having a diverse cellular distribution, TF is involved in many biological pathways and pathologies. Our earlier work identified host cell‐derived TF on the envelope covering several viruses, and showed its involvement in enhanced cell infection in vitro.
Objective
In the current study, we evaluated the in vivo effects of virus surface TF on infection and on the related modulator of infection PAR2.
Methods
With the use of herpes simplex virus type 1 (HSV1) as a model enveloped virus, purified HSV1 was generated with or without envelope TF through propagation in a TF‐inducible cell line. Infection was studied after intravenous inoculation of BALB/c, C57BL/6J or C57BL/6J PAR2 knockout mice with 5 × 10 plaque‐forming units of HSV1, mimicking viremia. Three days after inoculation, organs were processed, and virus was quantified with plaque‐forming assays and quantitative real‐time PCR.
Results
Infection of brain, lung, heart, spinal cord and liver by HSV1 required viral TF. Demonstrating promise as a therapeutic target, virus‐specific anti‐TF mAbs or small‐molecule inhibitors of coagulation inhibited infection. PAR2 modulates HSV1 in vivo as demonstrated with PAR2 knockout mice and PAR2 agonist peptide.
Conclusion
TF is a constituent of many permissive host cell types. Therefore, the results presented here may explain why many viruses are correlated with hemostatic abnormalities, and indicate that TF is a novel pan‐specific envelope antiviral target.
Keyword(s)
anticoagulant, coagulation, protease‐activated receptor, tissue factor, virus infection
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