Abstract
Cyclooxygenase-2 (COX-2) is one of the important mediators of inflammation in response to viral infection, and it contributes to viral replication, for example, cytomegalovirus or hepatitis C virus replication. The role of COX-2 in dengue virus (DENV) replication remains unclear. In the present study, we observed an increased level of COX-2 in patients with dengue fever compared with healthy donors. Consistent with the clinical data, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. Using cell-based experiments, we revealed that DENV-2 infection significantly induced COX-2 expression and prostaglandin E2 (PGE2) production in human hepatoma Huh-7 cells. The exogenous expression of COX-2 or PGE2 treatment dose-dependently enhanced DENV-2 replication. In contrast, COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. In an ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection. By using COX-2 promoter-based analysis and specific inhibitors against signaling molecules, we identified that NF-κB and MAPK/JNK are critical factors for DENV-2-induced COX-2 expression and viral replication. Altogether, our results reveal that COX-2 is an important factor for DENV replication and can serve as a potential target for developing therapeutic agents against DENV infection.
Highlights
Dengue virus (DENV) is a rapidly spreading mosquito-borne viral disease that is dispersed throughout the tropical and subtropical world[1]
Elevated levels of COX-2 RNA and PGE2 were observed in 11 out of 13 patients with dengue fever (DF), compared with the group of healthy donors (Fig. 1A and B). These patients were diagnosed with dengue hemorrhagic fever (DHF), and 10 out of 11 patients presented with plasma leakage, which exhibited higher COX-2 and PGE2 levels
We suggested that the levels of COX-2 and PGE2 production might correlate with the severity of the disease
Summary
Dengue virus (DENV) is a rapidly spreading mosquito-borne viral disease that is dispersed throughout the tropical and subtropical world[1]. Several reports have shown that the suppression of COX-2 expression and PGE2 production by selective COX-2 inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) has an antiviral effect, attenuating disease severity in, for example, herpes simplex virus (HSV)[14], influenza H5N115, Japanese encephalitis virus (JEV)[16], EV7117, and HCV infections[18]. The role of COX-2/PGE2 in DENV replication remains to be investigated. The level of COX-2 and its product PGE2 induced by DENV infection were quantified at different time points and viral loads. The effects of exogenous COX-2 expression or added PGE2 on DENV replication were determined. COX-2 short hairpin RNA (shRNA) and the specific inhibitor NS398 were used to determine whether COX-2 plays an important role in DENV replication. The effect of a COX-2-specific inhibitor on an ICR suckling mouse model was investigated to evaluate the potency of COX-2 as a therapeutic target against DENV infection
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