Tumor necrosis factor a (TNF-α) is the hub regulator of the inflammatory responses in many viral infections. The introduction of TNF-α blocking therapy with antibodies and/or antagonists has been a new era in the treatment of inflammatory human disease with high medical demand. Pro-inflammatory TNF-α facilitates dengue virus (DENV) infection in endovascular dysfunction and neurotoxicity. This study aims to investigate the protective role of TNF-α blockade in dengue encephalitis. According to the results, TNF-α was produced in vivo by microglia and astrocytes around the hippocampus in the brains of DENV infection. DENV directly caused neurotoxicity in vitro and combined treatment of TNF-α effectively facilitated DENV-induced neuronal cell death. By using a currently established encephalitic mice model that DENV infection causes progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days post-infection, administration of neutralizing TNF-α antibody reduced dengue encephalitis and mortality. These results demonstrate an immunopathogenesis of TNF-α for mediating DENV-induced encephalitis-associated neurotoxicity and targeting TNF-α as a strategy against dengue encephalitis.
This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST106-2321-B-038 -002), and the intramural funding 105TMU-CIT-01-2, Taiwan.