Essential Role of Platelet-Activating Factor Receptor in the Pathogenesis of Dengue Virus Infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-08, Vol.106 (33), p.14138-14143
• Main Authors: Souza, Danielle G., Fagundes, Caio T., Sousa, Lirfandia P., Amaral, Flavio A., Souza, Rafael S., Souza, Adriano L., Kroon, Erna G., Sachs, Daniela, Cunha, Fernando Q., Bukin, Eugenij, Atrasheuskaya, Alena, Ignatyev, George, Teixeira, Mauro M., Ferreira, Sérgio Henrique
• Format: Article
• Language: English
• Subjects: Aedes; Animals; Biological Sciences; Blood; Brain - metabolism; Brain - virology; Cell Line; Cells; Cytokines; Cytokines - metabolism; Dengue; Dengue - metabolism; Dengue - virology; Dengue fever; Dengue virus; Dengue Virus - metabolism; Dihydropyridines - pharmacology; Disease Models, Animal; Humans; Imidazoles - pharmacology; Infections; Inoculation; Leukocytes; Liver; Mice; Mice, Inbred BALB C; Permeability; Platelet Membrane Glycoproteins - antagonists & inhibitors; Platelet Membrane Glycoproteins - physiology; Platelets; Proteins; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - physiology; Rodents; Spleen; Vector-borne diseases; Viral Load; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0906467106

Severe dengue infection in humans causes a disease characterized by thrombocytopenia, increased levels of cytokines, increased vascular permeability, hemorrhage, and shock. Treatment is supportive. Activation of platelet-activating factor (PAF) receptor (PAFR) on endothelial cells and leukocytes induces increase in vascular permeability, hypotension, and production of cytokines. We hypothesized that activation of PAFR could account for the major systemic manifestations of dengue infection. Inoculation of adult mice with an adapted strain of Dengue virus caused a systemic disease, with several features of the infection in humans. In $PAFR^{ - / - } $ mice, there was decreased thrombocytopenia, hemoconcentration, decreased systemic levels of cytokines, and delay of lethality, when compared with WT infected mice. Treatment with UK-74,505, an orally active PAFR antagonist, prevented the above-mentioned manifestations, as well as hypotension and increased vascular permeability, and decreased lethality, even when started 5 days after virus inoculation. Similar results were obtained with a distinct PAFR antagonist, PCA-4246. Despite decreased disease manifestation, viral loads were similar $(PAFR^{ - / - }) $ or lower (PAFR antagonist) than in WT mice. Thus, activation of PAFR plays a major role in the pathogenesis of experimental dengue infection, and its blockade prevents more severe disease manifestation after infection with no increase in systemic viral titers, suggesting that there is no interference in the ability of the murine host to deal with the infection. PAFR antagonists are diseasemodifying agents in experimental dengue infection.