title: Human cytomegalovirus-platelet interaction triggers toll-like receptor 2-dependent proinflammatory and proangiogenic responses.
abstract: OBJECTIVE
  Human cytomegalovirus (HCMV) is a widespread pathogen that correlates with various clinical complications, including atherosclerosis. HCMV is released into the circulation during primary infection and periodic viral reactivation, allowing virus-platelet interactions. Platelets are important in the onset and development of atherosclerosis, but the consequences of platelet-HCMV interactions are unclear.
  
  
  RESULTS
  We studied the effects of HCMV-platelet interactions in blood from healthy donors using the purified clinical HCMV isolate VR1814. We demonstrated that HCMV bound to a Toll-like receptor (TLR) 2-positive platelet subpopulation, which resulted in signal transduction, degranulation, and release of proinflammatory CD40L and interleukin-1β and proangiogenic vascular endothelial-derived growth factor. In mice, murine CMV activated wild-type but not TLR2-deficient platelets. However, supernatant from murine CMV-stimulated wild-type platelets also activated TLR2-deficient platelets, indicating that activated platelets generated soluble mediators that triggered further platelet activation, independent of TLR2 expression. Inhibitor studies, using ADP receptor antagonists and apyrase, revealed that ADP release is important to trigger secondary platelet activation in response to HCMV. HCMV-activated platelets rapidly bound to and activated neutrophils, supporting their adhesion and transmigration through endothelial monolayers. In an in vivo model, murine CMV induced systemic upregulation of platelet-leukocyte aggregates and plasma vascular endothelial-derived growth factor in mice and showed a tendency to enhance neutrophil extravasation in a TLR2-dependent fashion.
  
  
  CONCLUSIONS
  HCMV is a well-adapted pathogen that does not induce immediate thrombotic events. However, HCMV-platelet interactions lead to proinflammatory and proangiogenic responses, which exacerbate tissue damage and contribute to atherogenesis. Therefore, platelets might contribute to the effects of HCMV in accelerating atherosclerosis.
authors.affiliation: From the Department of Medicine, Centre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (A.A., K.C.Y., E.K., Y.W., A.-A.M., P.R., A.R., L.M.B., C.S.-N.); Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (A.A., J.B.K., W.C.S., G.S.); Postgraduate School of Molecular Medicine, Department of Internal Medicine and Hypertension, Medical University of Warsaw, Warsaw, Poland (E.K.); and Department of Geriatrics, Qilu Hospital, Shandong University, Jinan, China (Y.W.).
authors.forename: Alice
authors.initials: A
authors.lastname: Assinger
authors.forename: Julia B
authors.initials: JB
authors.lastname: Kral
authors.forename: Koon C
authors.initials: KC
authors.lastname: Yaiw
authors.forename: Waltraud C
authors.initials: WC
authors.lastname: Schrottmaier
authors.forename: Ewa
authors.initials: E
authors.lastname: Kurzejamska
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Abdul-Aleem
authors.initials: AA
authors.lastname: Mohammad
authors.forename: Piotr
authors.initials: P
authors.lastname: Religa
authors.forename: Afsar
authors.initials: A
authors.lastname: Rahbar
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Butler
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Naucler
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000821:virology; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D023201:CD40 Ligand / Q000378:metabolism; D015550:Cell Degranulation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000472:pathogenicity*; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015539:Platelet Activation / Q000187:drug effects; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D058921:Purinergic P2Y Receptor Antagonists; D018048:Receptors, Purinergic P2; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D023201:CD40 Ligand; D000244:Adenosine Diphosphate
keywords: atherosclerosis; blood platelets; cytomegalovirus; toll-like receptors