title: Emerging concepts in dengue pathogenesis: interplay between plasmablasts, platelets, and complement in triggering vasculopathy.
abstract: Dengue is a mosquito-borne disease caused by infection with dengue virus (DENV) that represents a serious and expanding global health threat. Most DENV infections are inapparent or produce mild and self-limiting illness; however a significant proportion results in severe disease characterized by vasculopathy and plasma leakage that may culminate in shock and death. The cause of dengue-associated vasculopathy is likely to be multifactorial but remains essentially unknown. Severe disease is manifest during a critical phase from 4 to 7 days after onset of symptoms, once the virus has disappeared from the circulation but before the peak of T-cell activation, suggesting that other factors mediate vasculopathy. Here, we present evidence for a combined role of plasmablasts, complement, and platelets in driving severe disease in DENV infection. Massive expansion of virus-specific plasmablasts peaks during the critical phase of infection, coincident with activation of complement and activation and depletion of platelets. We propose a step-wise model in which virus-specific antibodies produced by plasmablasts form immune complexes, leading to activation of complement and release of vasoactive anaphylatoxins. Platelets become activated through binding of complement- and antibody-coated virus, as well as direct binding of virus to DC-SIGN, leading to the release of inflammatory microparticles and cytokines and sequestration of platelets in the microvasculature. We suggest that the combined effects of anaphylatoxins, inflammatory microparticles, and platelet sequestration serve as triggers of vasculopathy in severe dengue.
authors.affiliation: Center for Vaccine Research and Departments of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Eduardo J M
authors.initials: EJ
authors.lastname: Nascimento
authors.affiliation: Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz, and Instituto de Pesquisa Clinica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Eugenio D
authors.initials: ED
authors.lastname: Hottz
authors.affiliation: Departments of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Garcia-Bates
authors.affiliation: Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bozza
authors.affiliation: Center for Vaccine Research and Departments of Infectious Diseases and Microbiology, University of Pittsburgh, Pennsylvania, USA; Departmento de Virologia e Terapia Experimental, Centro de Pesquisas Aggeu Magalhaes, Fundacao Oswaldo Cruz, Brazil.
authors.forename: Ernesto T A
authors.initials: ET
authors.lastname: Marques
authors.affiliation: University of Pittsburgh.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Barratt-Boyes
mesh_terms: D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D003715:Dengue / Q000209:etiology*; D003716:Dengue Virus / Q000276:immunology*; D006801:Humans; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D015539:Platelet Activation / Q000276:immunology
chemical_list: D003165:Complement System Proteins