Platelet proteome reveals novel pathways of platelet activation and platelet-mediated immunoregulation in dengue

PLoS Pathogens

Eugenio Damaceno Hottz¹  Fernando A. Bozza²  Jonas Perales³  André Teixeira-Ferreira⁴  Patrícia T. Bozza⁵  Giselle Villa Flor Brunoro⁵  Guy A. Zimmerman⁶  Gustavo Adolfo Salazar⁷  Monique Ramos de Oliveira Trugilho⁷  Paulo Costa Carvalho⁷ 

[1] Centro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;Computational Biology Group, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States of America;Laboratório de Análise de Glicoconjugados, Departamento de Bioquímica, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, Minas Gerais, Brazil;Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;Laboratório de Proteômica e Engenharia de Proteínas, Instituto Carlos Chagas (ICC), Fiocruz, Curitiba, Paraná, Brazil;Laboratório de Toxinologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil

关键词: Platelets;    Platelet activation;    Dengue fever;    Histones;    Proteomes;    Blood plasma;    Proteasomes;    Chemokines;   

DOI  :  10.1371/journal.ppat.1006385

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Dengue is the most prevalent human arbovirus disease worldwide. Dengue virus (DENV) infection causes syndromes varying from self-limiting febrile illness to severe dengue. Although dengue pathophysiology is not completely understood, it is widely accepted that increased inflammation plays important roles in dengue pathogenesis. Platelets are blood cells classically known as effectors of hemostasis which have been increasingly recognized to have major immune and inflammatory activities. Nevertheless, the phenotype and effector functions of platelets in dengue pathogenesis are not completely understood. Here we used quantitative proteomics to investigate the protein content of platelets in clinical samples from patients with dengue compared to platelets from healthy donors. Our assays revealed a set of 252 differentially abundant proteins. In silico analyses associated these proteins with key molecular events including platelet activation and inflammatory responses, and with events not previously attributed to platelets during dengue infection including antigen processing and presentation, proteasome activity, and expression of histones. From these results, we conducted functional assays using samples from a larger cohort of patients and demonstrated evidence for platelet activation indicated by P-selectin (CD62P) translocation and secretion of granule-stored chemokines by platelets. In addition, we found evidence that DENV infection triggers HLA class I synthesis and surface expression by a mechanism depending on functional proteasome activity. Furthermore, we demonstrate that cell-free histone H2A released during dengue infection binds to platelets, increasing platelet activation. These findings are consistent with functional importance of HLA class I, proteasome subunits, and histones that we found exclusively in proteome analysis of platelets in samples from dengue patients. Our study provides the first in-depth characterization of the platelet proteome in dengue, and sheds light on new mechanisms of platelet activation and platelet-mediated immune and inflammatory responses.

【 授权许可】

CC BY