Regular ArticleThe Procoagulant Envelope Virus Surface: Contribution to Enhanced Infection
Introduction
Many types of virus acquire a covering as they “bud” from the host cell. This structure, called an envelope, consists of a cell-derived lipid bilayer and the associated membrane-bound proteins, which are encoded by both viral and host genes. Since the host cell and the respective membrane are not constant, the envelope proteome is variable, and consequently the roles of host-encoded envelope proteins in the virus life-cycle and pathology are poorly understood. Numerous enveloped viruses affect hemostasis, such as herpes simplex virus types 1 (HSV1) [1] and 2 [2], cytomegalovirus [3], dengue virus [4], Ebola virus [5], hepatitis C virus [6], human immunodeficiency viruses 1 and 2 [7] and influenza virus [8]. As a model envelope virus, our focus has been primarily on HSV1, which uses host- and virus-encoded proteins to activate plasma coagulation proteases on its surface. Here we review our studies showing that HSV1 envelope receptors exploit these proteases to enhance cellular infection by triggering host signaling mechanisms.
Section snippets
Envelope Procoagulant Phospholipid
The essential roles of thrombin in biology are highly regulated, requiring procoagulant phospholipid (proPL; e.g. phosphatidylserine) as a focal point for binding and assembly of the enzyme-cofactor-substrate complex that activates its precursor, prothrombin, and upstream proteases. ProPL serves to localize and concentrate clotting proteins to sites of vascular damage, where agonists induce its controlled accessibility. In contrast, we showed that purified HSV1, and other members of the herpes
Coagulation Proteases Increase HSV1 Infection
Thrombin, FVIIa, FXa and other proteases such as fibrinolytic plasmin, stimulate many cell types by exposing a “tethered-ligand” at the N-terminus of G-protein-linked protease activated receptors (PARs) [19]. Due to the procoagulant enzymes generated on the HSV1 envelope, we consequently investigated a role for host cellular PAR1 and PAR2 in infection (Fig. 1). Using purified proteases, synthetic PAR-activating peptides and inhibitory antibodies to PAR-mediated signaling, we showed that
Conflict of Interest Statement
The authors have no conflicts to declare of relevance to this work.
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