Dietary manganese potentiates BmNPV resistance in silkworms via BmcGLR-mediated activation of BmRelish through BmSTING.

The silkworm (Bombyx mori) is a vital economic species threatened by Bombyx mori nucleopolyhedrovirus (BmNPV), causing severe losses in sericulture. Here, we demonstrate that dietary Mn2+ supplementation enhances silkworm resistance to BmNPV. Transcriptomic analysis and RT-qPCR validation revealed Mn2+-dependent upregulation of Relish-mediated antimicrobial peptides. We identified a cGAS-like receptor (BmcGLR) in B. mori, highly expressed in hemocytes and structurally poised for Mn2+ binding. Mn2+ directly stimulated BmcGLR to amplify -2',3'-cGAMP production, which activated BmSTING-dependent antiviral signaling. Knockdown of BmcGLR or BmSTING attenuated Mn2+-induced suppression of viral proliferation and downregulated Relish target genes. Further experiments showed that BmRelish inhibition abolished Mn2+-driven upregulation of BmcGLR, BmSTING, and effector genes, while bioinformatic analysis predicted a Relish-binding site in BmcGLR's first intron, suggesting a positive feedback loop. Our findings establish Mn2+ as an immunostimulant that bolsters antiviral defense via the BmcGLR-cGAMP-BmSTING-BmRelish axis, offering a sustainable strategy for BmNPV control in sericulture.