Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection

Abstract

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.inflammation ͉ cytokines ͉ shock

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

“…In fact, the absence or antagonism of PAFR causes significant protection against bacterial translocation through intestinal epithelial cells (26) and influenza A-associated lethality (27), PAFR contributes to cancer progression and metastasis (28), and activation of PAFR plays a major role in the pathogenesis of experimental Dengue infection (29). If C/EBPδ also induced PAFR levels in these disorders, it might be a potential target for therapeutic modulation.…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…with serial dilutions of the virus, and lethality was recorded as described previously. [45][46][47] The titer of DENV stock was 10 5 LD 50 /mL, or 2 ϫ 10 6 plaque-forming units (PFUs)/mL based on plaque assay on LLC-MK2 cells.…”

“…Hematocrit concentration and extravasation of Evans blue dye into the tissues was used as an index of increased vascular permeability, as previously described. 45,48 A portion of liver was obtained from mice euthanized at day 6 and was immediately fixed in 4% buffered formalin, and tissue fragments were embedded in paraffin. Tissue sections 4 m thick were stained using H&E and examined under light microscopy for inflammatory changes using a semiquantitative score.…”

Production of intravenous human dengue immunoglobulin from Brazilian-blood donors

“…All four virus serotypes cause a spectrum of illness ranging from asymptomatic or mild febrile disease to classical dengue fever (DF) and to more severe disease manifesting as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) (Souza et al, 2009). The severity of the disease is likely to depend on various factors, including the strain and serotype of the infecting virus, the age and genetic background of the patient and the degree of viremia (Guzman, Kouri, 2002;Vaughn et al, 2000).…”