Abstract Brucellosis is a widespread zoonotic disease caused by Brucella, a genus of facultative intracellular bacteria that infects livestock and humans. Brucella primarily replicates within the endoplasmic reticulum (ER) of host cells, where it establishes a specialized replicative niche. This ER localization disrupts ER structure and induces ER stress. The unfolded protein response (UPR) is a critical cellular pathway that maintains ER homeostasis by restoring protein-folding capacity and regulating stress responses. However, how Brucella manipulates host UPR pathways to promote its intracellular survival and pathogenesis remains poorly understood. Here, we identify the Brucella outer membrane protein Omp25 as a key factor in promoting its intracellular survival and proliferation by activating the host UPR. Omp25 directly binds to the ER chaperone Binding-immunoglobulin protein (BiP), inducing the release and activation of the UPR sensors PERK (PKR-like ER kinase), IRE1α (inositol requiring enzyme 1 alpha), and ATF6 (activating transcription factor 6), thereby modulating ER homeostasis to favor bacterial replication. Additionally, Omp25 enhances inflammatory cytokine expression via the BiP-IRE1α-NF-κB signaling axis. The omp25-deleted strains (Δomp25) show impaired intracellular replication and reduced UPR activation, and result in attenuated induction of inflammatory genes in infected cells compared to wild-type strains. In vivo, mice infected with an omp25 mutant strain exhibit lower bacterial burdens and milder tissue pathology compared to mice infected with the wild-type strain. These findings uncover a mechanism by which Omp25 facilitates Brucella intracellular proliferation through UPR modulation and highlight Omp25 as a potential target for therapeutic interventions and next-generation attenuated vaccines.
Yang et al. (2026) studied this question.