A Broad-Spectrum Antiviral Target: The Host Cell-Derived Coagulation Initiator on the Virus, Tissue Factor

Abnormal blood clotting is a leading cause of death worldwide and many viruses are known to tip its normal balance. Furthering our understanding of the virus-clotting link, our lab discovered that the cell membrane coagulation initiator and inflammatory protein, tissue factor (TF), is integrated into the outer envelope of oral herpes virus and is required for infection in animals. Here we examine two widespread viruses from distinct families, Human coronavirus 229E (HCoV-229E) and dengue virus (DENV), to study whether TF is general to infection and disease progression. HCoV-229E is inflammatory, causing ~1/3 of common cold, and may escalate to pneumonia. Infecting ~400 million people annually, DENV can result in uncontrollable bleeding partly through consumption of the clotting factors. Like oral herpes, is TF common to both HCoV-229E and DENV, whose inhibition could reduce infection and prevent clotting-related deaths? To answer whether HCoV-229E and DENV contain TF, electron microscopy confirmed TF is associated with the surface of purified HCoV-229E and DENV. Demonstrating the known TF cofactor activity is present, purified virus accelerated clotting protein activation. These results indicated that TF resides on HCoV-229E and DENV in its active state, producing procoagulant enzymes, which moonlight in inflammation. The chemical on-switch for TF in clotting is the formation of a special chemical bond. This is aided by a cellular enzyme, and drugs that block this enzyme are already approved for use. Focusing on how well DENV forms a clot and infects cells with non-active TF on its surface, I will re-purpose this drug and propagate DENV in their presence. Furthermore, a TF deficient virus is being produced in a TF-deficient cell using molecular engineering. The effects on purified DENV surface TF clotting function and contribution to infection will be assessed in cell and animal models to define a novel broad-spectrum antiviral anticoagulant therapeutic.