Neuromedin B and its receptor NMBR inhibit H9N2 infection

Neuromedin B (NMB) and its receptor NMBR constitute a neuropeptide system implicated in various physiological processes. While previously associated with innate immunity, their precise antiviral action against influenza A virus (IAV) infection have remained poorly defined. Here, we elucidate the function of the NMB/NMBR axis in the host defense against H9N2 influenza virus. We demonstrate that NMB treatment and NMBR overexpression potentiate IFN-β production and restrict viral replication in H9N2-infected A549 cells and mouse lungs. Conversely, NMBR knockdown compromises the antiviral response, diminishing IFN-β expression and enhancing viral propagation. We further show that NMB/NMBR signaling targets the viral non-structural protein 1 (NS1) by upregulating the E3 ubiquitin ligase TRIM25. Mechanistically, NMB/NMBR activation engages a positive feedback loop with the retinoic acid-inducible gene I (RIG-I) pathway, reinforcing RIG-I activation through enhanced K63-linked ubiquitination while transcriptionally repressing the deubiquitinase CYLD. Consequently, this augmented signaling potentiates the JAK-STAT1 pathway, leading to increased STAT1 phosphorylation and elevated expression of interferon-stimulated gene 15 (ISG15). Our findings establish that the NMB/NMBR axis confers protection against H9N2 IAV by amplifying RIG-I-mediated innate immunity and facilitating NS1 suppression, revealing a pivotal neuroimmune mechanism and suggesting a promising target for developing broad-spectrum, host-directed therapeutics against IAV.