Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/46493

Type
Article
Copyright
Open access
Collections
Share

Statistics
Metadata
Show full item record

CONTACT SYSTEM ACTIVATION IN PLASMA FROM DENGUE PATIENTS MIGHT HARNESS ENDOTHELIAL VIRUS REPLICATION THROUGH THE SIGNALING OF BRADYKININ RECEPTORS
Coelho, Sharton V. A. et al. | Date Issued: 2021
Author
Coelho, Sharton V. A.
Rusr, Naiara M.
Vellasco, Lucas
Papa, Michelle P.
Pereira, Aline S. G.
Palazzo, Matheus Ferreira da Silva
Juliano, Maria Aparecida
Costa, Simone M.
Alves, Ada M. B.
Cordeiro, Marli T.
Marques, Ernesto T. A.
Scharfstein, Júlio
Arruda, Luciana B. de
Affilliation
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Virologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Virologia. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Virologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Virologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal de São Paulo. Escola Paulista de Medicina. Departamento de Biofísica. São Paulo, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biotecnologia e Fisiologia de Infecções Virais. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biotecnologia e Fisiologia de Infecções Virais. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.
Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil / University of Pittsburgh. Department of Infectious Diseases. Pittsburgh. PA, USA.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Virologia. Rio de Janeiro, RJ, Brasil.
Abstract
Abstract: Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable levels of activated plasma kallikrein (PKa) in the large majority of samples from a dengue cohort (n = 70), irrespective of severity of clinical symptoms. Impaired formation of PKa in dengue-plasmas correlated with the presence of cleaved Factor XII and high molecular weight kininogen (HK), suggesting that the prothrombogenic contact system is frequently triggered during the course of infection. Using two pathogenic arboviruses, DENV or Zika virus (ZIKV), we then asked whether exogenous BK could influence the outcome of infection of human brain microvascular endothelial cells (HBMECs). Unlike the unresponsive phenotype of Zika-infected HBMECs, we found that BK, acting via B2R, vigorously stimulated DENV-2 replication by reverting nitric oxide-driven apoptosis of endothelial cells. Using the mouse model of cerebral dengue infection, we next demonstrated that B2R targeting by icatibant decreased viral load in brain tissues. In summary, our study suggests that contact/KKS activation followed by BK-induced enhancement of DENV replication in the endothelium may underlie microvascular pathology in dengue.
Keywords in Portuguese
Dengue
Bradykinin
Células endoteliais
Caminho de contato
Bradykinin receptor B2
Sistema Kallikrein-kinin
 
Keywords
Dengue
Bradykinin
Endothelial cells
Kallikrein-kinin system
Contact pathway
Bradykinin receptor B2
 
Publisher
MDPI
Citation
COELHO, Sharton V. A. et al. Contact System Activation in Plasma from Dengue Patients Might Harness Endothelial Virus Replication through the Signaling of Bradykinin Receptors. Pharmaceuticals, v. 14, n. 56, p. 1-27, 2021.
DOI
10.3390/ph14010056
ISSN
1424-8247