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ISSN 打印: 1040-8401
ISSN 在线: 2162-6472

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DOI: 10.1615/CritRevImmunol.2014010212
pages 227-240

Emerging Concepts in Dengue Pathogenesis: Interplay between Plasmablasts, Platelets, and Complement in Triggering Vasculopathy

Eduardo J. M. Nascimento
Center for Vaccine Research and Departments of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Eugenio D. Hottz
Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz, and Instituto de Pesquisa Clinica Evandro Chagas, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil
Tatiana M. Garcia-Bates
Departments of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Fernando Bozza
Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz
Ernesto T. A. Marques, Jr.
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
Simon M. Barratt-Boyes
University of Pittsburgh

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.