Cordycepin an Adenosine Analogue Executes Anti Rotaviral Effect by Stimulating Induction of Type I Interferon

Abstract

Abstract Objectives: Rotavirus is the single most common etiological pathogen of severe diarrhea in infants causing death of over half a million infants a year. In spite of such a huge disease burden, still no effective antivirals are available against rotavirus. Cordycepin (3’-deoxyadenosine), an adenosine analogue, has been reported to modulate cell proliferation, platelet aggregation and provide protection against HIV infection. Herein, attempts were made to analyze efficacy of cordycepin for protection against rotavirus and underlying mechanism. Methods Cordycepin’s anti-rotaviral activity was elucidated against simian rotavirus strain SA11 (H96), rhesus strain RRV, human strain Wa (in vitro) and murine strain EW (in BALB/c). Plaque assay, qPCR for viral transcripts and immunoblotting of viral proteins were done to examine viral abundance. Effect of cordycepin on Interferon pathway was analyzed by immunoblotting, co-immunoprecipitation and molecular docking. Results Cordycepin was found to reduce propagation of different rotavirus strains such as SA11, RRV, Wa at 64μM with minimal cytotoxicity in vitro and EW in BALB/c mice. Protection was obtained upto 24 hours, after virus infection at both low and high multiplicity of infection. Sensitivity of rotavirus infection to Interferons has been documented. In cordycepin treated cells increased induction of Interferon and downstream antiviral proteins were observed. Cordycepin treatment leads to RIGI-MAVS interaction, IRF3 activation, and Interferon induction. By using different software probable docking sites and orientation of cordycepin and RIG-I were predicted. Cordycepin was found to have relatively higher binding probability for ATP binding domain than other domains. In Vero cells,deficient in Interferon signalling, cordycepin failed to protect against rotavirus. This suggests that though cordycepin may have other effects but anti-rotaviral effects were due to boosting of cellular innate immune responses mediated by Interferon. Conclusions Overall this study highlights that cordycepin exerts its anti-rotaviral activity by modulating immune signalling through enhanced Interferon production.