Anti-Tnf-Alpha Restricts Dengue Virus-Induced Neuropathy

Proinflammatory TNF- facilitates dengue virus (DENV) infection in endovascular dysfunction and neurotoxicity. The introduction of TNF- blocking therapy with Abs is performed to test its therapeutic effect in this study. In DENV-infected mice, TNF- production in the brain accompanied the progression of neurotoxicity and encephalitis. DENV infection caused the loss of hippocampal neurons with TNF- expression around damaged regions, and immunostaining showed the induction of apoptosis in hippocampal neurons. TNF- was expressed in active microglia and astrocytes in DENV-infected mice. TNF- facilitated DENV-induced neurotoxicity in vitro in murine Neuro-2a cells. Using a currently established encephalitic mouse model in which DENV infection causes progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days postinfection, we showed that TNF- transgenic mice represented the progressive disease development and administration of neutralizing TNF- Ab reduced dengue encephalitis and mortality. These results demonstrate an immunopathogenesis of TNF- for mediating DENV-induced encephalitis-associated neurotoxicity and that targeting TNF- can be used as a strategy against dengue encephalitis.