title: Microparticles provide a novel biomarker to predict severe clinical outcomes of dengue virus infection.
abstract: Shedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces. Ex vivo analysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1-anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP shedding in vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever.
  
  
  OBJECTIVE
  Dengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care.
authors.affiliation: Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand.
authors.forename: Nuntaya
authors.initials: N
authors.lastname: Punyadee
authors.affiliation: Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand Medical Biotechnology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand.
authors.forename: Dumrong
authors.initials: D
authors.lastname: Mairiang
authors.affiliation: Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand.
authors.forename: Somchai
authors.initials: S
authors.lastname: Thiemmeca
authors.affiliation: Division of Clinical Epidemiology, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand.
authors.forename: Chulaluk
authors.initials: C
authors.lastname: Komoltri
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Rajthevee, Bangkok, Thailand.
authors.forename: Wirichada
authors.initials: W
authors.lastname: Pan-Ngum
authors.affiliation: Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand.
authors.forename: Nusara
authors.initials: N
authors.lastname: Chomanee
authors.affiliation: Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand.
authors.forename: Komgrid
authors.initials: K
authors.lastname: Charngkaew
authors.affiliation: Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand Medical Biotechnology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand.
authors.forename: Nattaya
authors.initials: N
authors.lastname: Tangthawornchaikul
authors.affiliation: Pediatric Department, Songkhla Hospital, Ministry of Public Health, Songkhla, Thailand.
authors.forename: Wannee
authors.initials: W
authors.lastname: Limpitikul
authors.affiliation: Pediatric Department, Khon Kaen Hospital, Ministry of Public Health, Khon Kaen, Thailand.
authors.forename: Sirijitt
authors.initials: S
authors.lastname: Vasanawathana
authors.affiliation: Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand Medical Biotechnology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand.
authors.forename: Prida
authors.initials: P
authors.lastname: Malasit
authors.affiliation: Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok-noi, Bangkok, Thailand Medical Biotechnology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Bangkok, Thailand panisadee.avi@mahidol.ac.th.
authors.forename: Panisadee
authors.initials: P
authors.lastname: Avirutnan
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood*; D055252:Cell-Derived Microparticles / Q000737:chemistry* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D011379:Prognosis; D014759:Viral Envelope Proteins / Q000032:analysis; D017361:Viral Nonstructural Proteins / Q000032:analysis
chemical_list: D015415:Biomarkers; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins