Telmisartan impedes JEV infection predominately via AT1/PPARγ axis

ABSTRACT Japanese encephalitis, caused by Japanese encephalitis virus (JEV) is a vector born disease for which no specific therapeutics are available yet. Binding of angiotensin II (Ang II) to angiotensin II type 1 (AT1) receptor induces 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 in vitro and in vivo. TM reduced JEV titer, RNA and protein (NS3) significantly in the BHK-21 cells with IC 50 of 24.68μM and CC 50 of >350 μM (Selectivity Index >14.18) indicating its potential of repurposing against JEV. The anti-JEV efficacy of TM was further observed in macrophages (RAW264.7) and neuronal (SH-SY5Y) cells. Interestingly, the viral load was reduced significantly in pre, co and post-treatment conditions of TM, however most efficiently (80%) in post treatment. In presence of GW (PPARγ antagonist) and AG (AT1 agonist), viral infection was increased remarkably while AT1 was upregulated and PPARγ was downregulated. Whereas, TM treatment reversed the levels of AT1 and PPARγ during infection. Further, 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 mice 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.