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.
Highlights
Dengue is an infectious disease caused by four antigenically-related serotypes of dengue virus (DENV-1 to -4)
Thrombocytopenia is a hallmark of dengue, the molecular phenotype and activities of platelets in the pathogenesis of dengue is not well elucidated
This work characterizes the proteome of platelets isolated from patients with dengue and includes validation of functionally-linked protein networks that we identified, using samples from a larger cohort of dengue patients
Summary
Dengue is an infectious disease caused by four antigenically-related serotypes of dengue virus (DENV-1 to -4). It is the most frequent hemorrhagic viral disease and re-emergent infection in the world, with over 2.5 billion people living in high-risk transmission areas and more than 90 million apparent infections registered annually [1,2,3]. Besides well-known hemostatic activities, newly-recognized platelet functions mediate both immune protective activities, including pathogen sensing and host responses, and inflammatory and immune injury to the host [9,10,11]. It is increasingly recognized that activated platelets have a repertoire of mechanisms for immune effector activity including release of cytokines and interaction with leukocytes [9,12,13]. New discoveries of platelet biology of this type suggest that knowledge of global changes in platelet proteome, phenotype and function in dengue infection may contribute to a broader understanding of the pathobiology of dengue disease, as in other infections (9–11)
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