Correlation of inducible nitric oxide synthase (iNOS) inhibition with TNF-α, caspase-1, FasL and TLR-3 in pathogenesis of rabies in mouse model

Abstract

The role of inflammatory cytokines such as interleukin-1α/β (IL-1α/β), IL-6, IL-10, tumour necrosis factor-alpha (TNF-α), interferons, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in pathogenesis of rabies is being actively pursued. Presently, levels of certain immune molecules in pathogenesis of rabies in mice have been investigated. CVS strain of rabies infection resulted in early increase in iNOS, TNF-α, caspase-1, Fas ligand (FasL) and toll-like receptor-3 (TLR-3) mRNA levels in brain, and nitric oxide levels in serum. The severity of clinical signs and microscopic lesions largely correlated with NO levels. Aminoguanidine (AG; iNOS inhibitor) decreased NO production with delay in development of clinical signs and increase in survival time. Prolonged survival time correlated with reduced viral load evident by real-time PCR, reduced fluorescent signals of rabies antigen in brain and reduced immunohistochemistry signals in neuronal cytoplasm. These parameters suggested that nitric oxide did influence the rabies virus replication. Inhibition of iNOS by AG administration led to decreased expression of TNF-α, caspase-1, FasL and TLR-3 mRNA levels suggesting that increase in NO levels in rabies virus infection possibly contributed to development of disease through inflammation, apoptosis and immune-evasive mechanisms.

Keywords: Aminoguanidine; Caspase-1; FasL; Rabies virus; TLR-3; TNF-α.