Platelets interact with Coxsackieviruses B and have a critical role in the pathogenesis of virus‐induced myocarditis

• Published in: Journal of thrombosis and haemostasis Vol. 13; no. 2; pp. 271 - 282
• Main Authors: Negrotto, S., Jaquenod de Giusti, C., Rivadeneyra, L., Ure, A. E., Mena, H. A., Schattner, M., Gomez, R. M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01-02-2015
• Subjects: Animals; Blood Platelets - immunology; Blood Platelets - metabolism; Blood Platelets - virology; Capsid Proteins - blood; Capsid Proteins - genetics; Cercopithecus aethiops; Coxsackievirus Infections - blood; Coxsackievirus Infections - immunology; Coxsackievirus Infections - virology; Disease Models, Animal; Enterovirus B, Human - genetics; Enterovirus B, Human - immunology; Enterovirus B, Human - metabolism; Enterovirus B, Human - pathogenicity; Female; Host-Pathogen Interactions; human enterovirus B; Humans; Immunoglobulin G - blood; Male; Medical research; Mice, Inbred C57BL; Myocarditis - blood; Myocarditis - immunology; Myocarditis - virology; P-Selectin - blood; Pathogenesis; Phosphatidylserines - blood; platelets; P‐selectin; RNA, Viral - blood; thrombocytopenia; Thrombocytopenia - blood; Thrombocytopenia - virology; Time Factors; Vero Cells; Viral infections; Virus Replication; human enterovirus B; pathogenesis; thrombocytopenia; P-selectin; platelets
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.12782

Summary
Background
To further understand the role of platelets in the pathogenesis of viral infections we explored platelet interaction with Coxsackieviruses B (CVB) 1 and 3. CVB is a group of viruses that cause the majority of human enterovirus‐related viral myocarditis; their receptor (CAR) is expressed on the platelet surface and there is a well‐characterized CVB3‐induced myocarditis murine model.
Methods
Human platelets were infected with CVB1 and 3 and viruses were detected in pellets and in supernatants. C57BL/6J mice with or without platelet depletion were inoculated with CVB3 and peripheral blood and heart samples collected at different times post‐infection.
Results
CVB1 and 3 RNA and a capsid protein were detected in infected platelets. Despite the fact that titration assays in Vero cells showed increasing infectivity titers over time, supernatants and pellets from infected platelets showed similar levels, suggesting that platelets were not susceptible to a replicative infectivity cycle. CVB binding was CAR‐independent and resulted in P‐selectin and phosphatidylserine (PS) exposure. CVB3‐infected mice showed a rapid thrombocytopenia that correlated with an increase in platelet PS exposure and platelet‐leukocyte aggregates without modification of platelet P‐selectin expression or von Willebrand factor levels. Mortality, viremia, heart viral titers and myocarditis were significantly higher in platelet‐depleted than normal animals. Type I IFN levels were not changed but IgG levels were lower in infected and platelet‐depleted mice.
Conclusions
Our data reveal that platelets play a critical role in host survival and immune response against CVB3 infection.