Brucella infection induces chromatin restructuring in host cells to activate immune responses

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Background Brucella spp., facultative intracellular pathogens that cause brucellosis, drive pathogenesis by invading host cells and establishing intracellular persistence. While their molecular mechanisms are well-characterized, how Brucella induces chromatin restructuring in host cells remains poorly understood, representing a critical gap in host-pathogen interaction research. Methods Using an established in vitro infection model of Brucella -infected RAW264.7 murine macrophages, we integrated Hi-C, ATAC-seq, and RNA-seq to generate multi-omics datasets. Multidimensional comparative genomics approaches were employed to systematically map infection-induced changes in host chromatin architecture and functional genomic organization. Results Our findings unveiled substantial alterations in the host chromatin architecture, characterized by a reduction in B-B compartment regions interactions, an increase in A-B compartment interactions, and diminished long-range chromatin contacts. Crucially, Brucella reshaped chromatin compartmentalization, activating interferon-stimulated genes (ISGs) in regions transitioning from compartment B to A. Enhanced sub-TADs interactions within ISG clusters further facilitated their coordinated expression. Additionally, infection remodeled chromatin loop structures, strengthening interactions linked to immune-related gene activation. Conclusion These results demonstrate that host cells undergo substantial chromatin remodeling during acute Brucella infection as a defense mechanism against pathogen invasion. Our findings provide critical insights into host-pathogen interactions and suggest potential epigenetic targets for managing brucellosis.