Key result
A 5' triphosphate-containing coxsackievirus B3 cloverleaf RNA structure potently induces RIG-I activation, eliciting an extensive antiviral response that protects cells against multiple viruses.
The 5'ppp-containing cloverleaf RNA structure from coxsackievirus B3 acts as a potent RIG-I agonist, triggering a broad-spectrum antiviral response in vitro.
Potent RIG-I agonist from CVB3 RNA suggests broad antiviral potential; leaves open in vivo efficacy and therapeutic translation.
Upon viral infections, pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate an antiviral state associated with the production of type I interferons (IFNs) and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. Although pegylated IFNs have been used to treat hepatitis B and C virus infections for decades, they exert substantial side effects that limit their use. Current efforts are directed toward the use of PRR agonists as an alternative approach to elicit host antiviral responses in a manner similar to that achieved in a natural infection. RIG-I is a cytosolic PRR that recognizes 5' triphosphate (5'ppp)-containing RNA ligands. Due to its ubiquitous expression profile, induction of the RIG-I pathway provides a promising platform for the development of novel antiviral agents and vaccine adjuvants. In this study, we investigated whether structured RNA elements in the genome of coxsackievirus B3 (CVB3), a picornavirus that is recognized by MDA5 during infection, could activate RIG-I when supplied with 5'ppp. We show here that a 5'ppp-containing cloverleaf (CL) RNA structure is a potent RIG-I inducer that elicits an extensive antiviral response that includes induction of classical interferon-stimulated genes, as well as type III IFNs and proinflammatory cytokines and chemokines. In addition, we show that prophylactic treatment with CVB3 CL provides protection against various viral infections including dengue virus, vesicular stomatitis virus and enterovirus 71, demonstrating the antiviral efficacy of this RNA ligand.
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Qian et al. (2014) studied Viral infection (in vitro models). Coxsackievirus B3 Cloverleaf RNA containing a 5' triphosphate vs. Mock treatment, other RNA fragments, or VSV hairpin was evaluated on IFN-beta promoter activation and antiviral protection. A 5' triphosphate-containing coxsackievirus B3 cloverleaf RNA structure potently induces RIG-I activation, eliciting an extensive antiviral response that protects cells against multiple viruses.
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