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

ABSTRACT: 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.

SUBMITTER: Trugilho MRO

PROVIDER: S-EPMC5453622 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Trugilho Monique Ramos de Oliveira MRO Hottz Eugenio Damaceno ED Brunoro Giselle Villa Flor GVF Teixeira-Ferreira André A Carvalho Paulo Costa PC Salazar Gustavo Adolfo GA Zimmerman Guy A GA Bozza Fernando A FA Bozza Patrícia T PT Perales Jonas J

PLoS pathogens 20170519 5

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. Neverthel ...[more]

PMID: 28542641

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Project description:Microglia, the resident immune cells of the brain, can exhibit a broad range of activation phenotypes, many of which have been implicated in several diseases and disorders of the central nervous system including those related to alcohol abuse. Given the complexity of global-scale molecular changes that define microglial activation, accurate phenotypic classification in the context of alcohol exposure is still lacking. We employed an optimized method for deep, quantitative proteome profiling of primary microglia in order to characterize their response to acute exposure to alcohol (ethanol) as well as the pro-inflammatory driver and TLR4 agonist, LPS. From this analysis, 5,062 total proteins were identified where 4,857 and 4,928 of those proteins were quantifiable by label-free quantitation in ethanol and LPS treatment groups, respectively. This study highlights the subtle, yet significant proteomic changes that occur in ethanol-treated microglia, which do not align with the robust pro-inflammatory phenotype induced by TLR4 activation. Specifically, our results indicate inhibition of several upstream regulators associated with inflammation, opposing effects on pathways such as phagocytosis upon comparison to TLR4-mediated pro-inflammatory phenotype, and a potential metabolic shift associated with increased expression of proteins related to OXPHOS and lipid homeostasis. Data are available via ProteomeXchange with identifier PXD14466. SIGNIFICANCE: Alcohol abuse has a significant impact on the central nervous system, which includes the pathophysiological mechanisms resulting from glial cell activation. Microglia, in particular, are the resident immune cells of the brain and exhibit a broad range of activation phenotypes. The molecular changes that drive microglial activation phenotype are complex and have yet to be fully characterized in the context of alcohol exposure. Our study highlights the first and most comprehensive characterization of alcohol-induced proteomic changes in primary microglia to date and has shed light on novel immune-related and metabolic pathways that are altered due to alcohol exposure. The results from this study provide an important foundation for future work aimed to understand the complexity of alcohol-induced microglial activation in vivo and other translational models of acute and chronic alcohol exposure.

Dataset Information

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

Publications

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

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