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| Interaction of platelets and viruses Ed Pryzdial. |
Abstract
The multifunctional role of platelets in haemostasis and the immune response is facilitated by diverse receptors on their surface. These receptors create opportunities for exploitation by viruses. Virus-platelet interactions can activate the platelet, induce coagulation pathways, and indirectly stimulate neighbouring leukocyte and endothelial cells, with potential harmful outcome. Virus infection often correlates to decreased platelet count (i.e. thrombocytopenia), caused by impact to the platelet or to their progenitor cells, megakaryocytes. To understand the effects of viruses on platelet number, we have been studying the highly prevalent, dengue virus (DENV), whose pathology is hallmarked by thrombocytopenia. We demonstrated that purified DENV binds directly to washed platelets via the receptors, dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin and heparan sulphate proteoglycan, with the number of binding sites enhanced by pretreatment of platelets with the haemostatic bioeffector, thrombin. Although anucleate, platelets have the translational machinery for producing proteins when given an RNA template, such as the DENV RNA genome. Denoting DENV entry into the cell, the virus-encoded non-structural protein 1 (NS1) is produced by DENV-inoculated platelets, and this production is further enhanced by platelet pretreatment with thrombin. NS1 production is also observed for DENV-inoculated megakaryocytic cells (MEG-01). Viable DENV was produced in leukoreduced platelet preparations. While purified NS1 has been reported to associate with platelets, we show that NS1 endogenously produced by inoculated platelets and MEG-01, associates with the cell surface. Interestingly, NS1 associates with inoculated MEG-01 in several configurations that involve colocalization with Hoechst-staining material, which is likely DNA. Neither commercial anti-NS1 nor patient plasma-derived antibodies cross-reacted with cellular protein disulfide isomerase, a previously proposed mechanism of thrombocytopenia. However, an alternate mechanism is indicated by our finding that NS1 expressed on DENV-inoculated MEG-01, correlates to the deposition of complement component C3 when treated with DENV-positive patient plasma. This C3 deposition was inhibited by purified NS1. In contrast, the alternative pathway of complement was induced by virus inoculation of MEG-01 independent of antibody and to a lesser extent by 10-day culture of non-infected cells. These data provide a direct mechanism leading to thrombocytopenia, where infection alters the surface of megakaryocytes, including virus antigen presentation. The resulting complement-mediated opsonization may favor destruction and clearance of megakaryocytes attenuating thrombopoiesis in DENV infection and contribute to reduced platelet count. Platelets may be similarly targeted by complement recognition of surface viral antigen.
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