Nature communicationsSep 28, 2026

A viral protein boosts self-replicating RNA by adjusting cell immune defense

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 30, 2026

Abstract

The Nodamura virus B2 protein enhances saRNA-driven transgene expression by alleviating antiviral responses.

Cis-expression of the Nodamura virus B2 protein may improve the effectiveness of saRNA vaccines.
In stem cells, NoV B2 reduces the buildup of small viral RNAs, which is linked to decreased antiviral responses.
In somatic cells, NoV B2 prevents a shutdown of protein production triggered by a cellular defense mechanism.
The B2 protein sequesters double-stranded RNA at the cell's edge, protecting it from immune responses.
This mechanism does not interfere with the production of type I interferon, which is crucial for immune signaling.

Simplified

Self-amplifying RNA (saRNA) offers a powerful approach for vaccine development, as its replicative nature within cells provides prolonged antigen expression together with self-adjuvanticity. However, its potency is often limited by innate immune responses, particularly those triggered by intracellular double-stranded RNA (dsRNA), highlighting the need for strategies that can boost saRNA efficacy without compromising its immunostimulatory properties. Here we show that the cis-expression of the Nodamura virus (NoV) B2 protein markedly enhances saRNA-driven transgene expression by alleviating key cell-intrinsic antiviral effectors. In stem cells, NoV B2 limits the accumulation of Dicer-generated viral small RNAs, consistent with suppression of antiviral RNA interference, while in somatic cells, it prevents protein kinase R (PKR)-driven translational shutdown. NoV B2 sequesters dsRNA at the cell periphery, shielding it from antiviral effectors without suppressing type I interferon induction or signalling, thereby preserving saRNA's immunostimulatory properties, while enhancing its transgene expression potential. These findings reveal a strategy to overcome intracellular antiviral restriction of saRNA while preserving adjuvanticity, with implications for the design of more effective saRNA-based vaccines and therapeutics.

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A viral protein boosts self-replicating RNA by adjusting cell immune defense

Abstract

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