Human cytomegalovirus-platelet interaction triggers toll-like receptor 2-dependent proinflammatory and proangiogenic responses

TY - JOUR

T1 - Human cytomegalovirus-platelet interaction triggers toll-like receptor 2-dependent proinflammatory and proangiogenic responses

AU - Assinger, Alice

AU - Kral, Julia B

AU - Yaiw, Koon C

AU - Schrottmaier, Waltraud C

AU - Kurzejamska, Ewa

AU - Wang, Yajuan

AU - Mohammad, Abdul-Aleem

AU - Religa, Piotr

AU - Rahbar, Afsar

AU - Schabbauer, Gernot

AU - Butler, Lynn M

AU - Söderberg-Naucler, Cecilia

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.APPROACH AND 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.

AB - 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.APPROACH AND 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.

KW - Adenosine Diphosphate

KW - Animals

KW - Atherosclerosis

KW - Blood Platelets

KW - CD40 Ligand

KW - Cell Degranulation

KW - Cells, Cultured

KW - Cytomegalovirus

KW - Humans

KW - Inflammation

KW - Inflammation Mediators

KW - Interleukin-1beta

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neovascularization, Pathologic

KW - Neutrophil Activation

KW - Neutrophils

KW - Platelet Activation

KW - Purinergic P2Y Receptor Antagonists

KW - Receptors, Purinergic P2

KW - Signal Transduction

KW - Time Factors

KW - Toll-Like Receptor 2

KW - Transendothelial and Transepithelial Migration

KW - Vascular Endothelial Growth Factor A

U2 - 10.1161/ATVBAHA.114.303287

DO - 10.1161/ATVBAHA.114.303287

M3 - SCORING: Journal article

C2 - 24558109

VL - 34

SP - 801

EP - 809

JO - ARTERIOSCL THROM VAS

JF - ARTERIOSCL THROM VAS

SN - 1079-5642

IS - 4

ER -