title: Dengue induces platelet activation, mitochondrial dysfunction and cell death through mechanisms that involve DC-SIGN and caspases.
abstract: BACKGROUND
  Worldwide, dengue is the most prevalent human arbovirus disease. Dengue infection may cause a range of clinical manifestations from self-limiting febrile illness through to a life-threatening syndrome accompanied by both bleeding and shock. Thrombocytopenia is frequently observed in mild and severe disease; however, the mechanisms involved in DENV-induced platelet activation and thrombocytopenia are incompletely understood.
  
  
  METHODS
  Freshly isolated platelets from patients with dengue were evaluated for markers of activation, mitochondrial alteration and activation of cell death pathways. In parallel, we examined direct DENV-induced activation and apoptosis of platelets obtained from healthy subjects.
  
  
  RESULTS
  We found that platelets from DENV-infected patients exhibited increased activation by comparison to control subjects. Moreover, platelets from DENV-infected patients exhibited classic signs of the intrinsic pathway of apoptosis that include increased surface phosphatidylserine exposure, mitochondrial depolarization and activation of caspase-9 and -3. Indeed, thrombocytopenia was shown to strongly associate with enhanced platelet activation and cell death in DENV-infected patients. Platelet activation, mitochondrial dysfunction and caspase-dependent phosphatidylserine exposure on platelets were also observed when platelets from healthy subjects were directly exposed to DENV in vitro. DENV-induced platelet activation was shown to occur through mechanisms largely dependent on DC-SIGN.
  
  
  CONCLUSIONS
  Together our results demonstrate that platelets from patients with dengue present signs of activation, mitochondrial dysfunction and activation of the apoptosis caspase cascade, which may contribute to the development of thrombocytopenia in patients with dengue. Our results also suggest the involvement of DC-SIGN as a critical receptor in DENV-dependent platelet activation.
authors: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors: E D
authors: ED
authors: Hottz
authors: M F
authors: MF
authors: Oliveira
authors: P C G
authors: PC
authors: Nunes
authors: R M R
authors: RM
authors: Nogueira
authors: R
authors: R
authors: Valls-de-Souza
authors: A T
authors: AT
authors: Da Poian
authors: A S
authors: AS
authors: Weyrich
authors: G A
authors: GA
authors: Zimmerman
authors: P T
authors: PT
authors: Bozza
authors: F A
authors: FA
authors: Bozza
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D020169:Caspases / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D003716:Dengue Virus / Q000502:physiology*; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology*; D015539:Platelet Activation / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D020169:Caspases; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin