Telmisartan, an anti-hypertensive drug, impedes JEV infection, possibly via the AT1/PPARγ axis

Japanese encephalitis, caused by Japanese encephalitis virus (JEV), is a vector-borne disease with no specific therapeutics available yet. Binding of angiotensin II (Ang II) to angiotensin II type 1 (AT1) receptor induces the release of inflammatory cytokines associated with viral encephalitis. Accordingly, Ang II receptor blockers (ARBs) have been proposed to manage encephalitis. Since telmisartan (TM, antagonist of AT1 and agonist of PPARγ) has relatively better brain access than other ARBs, this investigation aims to evaluate its anti-JEV efficacy <i>in vitro</i> and <i>in vivo</i>. TM reduced JEV titer, RNA, and protein (NS3) significantly in the BHK-21 cells with an IC₅₀ of 24.68 µM and a CC₅₀ of >350 µM (Selectivity Index >14.18), indicating its potential for repurposing against JEV. The anti-JEV efficacy of TM was further observed in other physiologically relevant cells. Interestingly, the viral load was reduced significantly in pre-, co-, and post-treatment conditions of TM. In the presence of GW (PPARγ antagonist) and AG (AT1 agonist), viral infection was increased remarkably, while AT1 was upregulated and PPARγ was downregulated. TM treatment reversed these levels during infection. In addition, siRNA knockdowns of AT1 and PPARγ showed an insignificant change in infection upon TM treatment. Furthermore, reduction of inflammatory markers like p-IRF-3, COX-2, and p-NF-κB was observed after TM treatment in RAW264.7 cells, suggesting its immunomodulation through the AT1/PPARγ axis. Finally, the anti-JEV potential of TM was validated in a mouse model through the reduction of disease score, viral protein, and histological changes. Thus, the preclinical efficacy of TM suggests its suitability for repurposing against JEV.IMPORTANCEJapanese encephalitis, caused by JEV, is a vector-borne disease for which no specific therapeutics are yet available. Binding of Ang II to the AT1 receptor induces the release of inflammatory cytokines associated with viral encephalitis. Accordingly, telmisartan, which is an antagonist of AT1 and an agonist of PPARγ with better brain access, was evaluated for its anti-JEV efficacy <i>in vitro</i> and <i>in vivo</i> in the current study. Telmisartan demonstrated significant reduction in JEV titer, RNA, and protein levels in different treatment conditions. This treatment reversed the levels of AT1 and PPARγ as well as inflammatory markers, p-IRF-3, COX-2, and p-NF-κB during JEV infection, suggesting its immunomodulatory effect through the AT1/PPARγ axis. Finally, the anti-JEV potential of telmisartan was validated in a mouse model through the reduction of disease score, viral protein, and histological changes. Hence, the preclinical efficacy of telmisartan suggests its suitability for repurposing against JEV.