Targeting Wnt Signaling and DNAJB6/MRJ-L as a Dual Anti-RSV Strategy: Insights into a Positive Regulatory Loop

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections, yet effective treatments are lacking. We found that the molecular chaperon DNAJB6/MRJ plays an essential role in RSV replication. Depletion of the long isoform of MRJ (MRJ-L) suppresses RSV replication. Transcriptomic analysis revealed that MRJ-L depletion downregulates Wnt signaling pathways. A pharmacological inhibitor of Wnt signaling suppressed RSV propagation and unexpectedly reduced MRJ-L expression, suggesting a positive regulatory loop between Wnt signaling and MRJ-L expression. Notably, simultaneous inhibition of Wnt signaling and MRJ-L additively suppressed RSV replication, suggesting that the Wnt-MRJ-L axis may serve as a new therapeutic target. This study provides insights into host-RSV interactions and potential antiviral strategies. Author SummaryThe molecular chaperone DNAJB6/MRJ has been implicated in the replication of respiratory syncytial virus (RSV), although the precise mechanisms remain unclear. In this study, we discovered that MRJ may influence RSV replication via Wnt signaling pathways. Specifically, we demonstrated that Wnt signaling inhibitor Wnt-C59 significantly reduced RSV replication by suppressing the synthesis of viral mRNA and genome/antigenome. Moreover, a positive feedback loop of the Wnt-MRJ axis may play a critical role in regulating RSV replication. Importantly, RSV replication was suppressed additively by inhibition of Wnt signaling and depletion of MRJ-L. Thus, a dual-targeted therapeutic approach may be effective in combating RSV infections.