Abstract
<title>Abstract</title> <p> Macrophages are central to antibacterial immunity, yet transcriptomic studies have predominantly examined individual bacterial infections, limiting understanding of the conserved and pathogen-specific principles governing macrophage responses. We performed a comparative transcriptomic analysis of phylogenetically diverse bacterial pathogens to identify shared host-defense programs and pathogen-specific transcriptional remodeling, not apparent from individual pathogen studies. Publicly available RNA-seq datasets were systematically screened using predefined inclusion criteria to identify comparable mouse bone marrow-derived macrophage infection models. Four datasets representing <italic>Mycobacterium tuberculosis</italic> , <italic>Coxiella burnetii</italic> , methicillin-resistant <italic>Staphylococcus aureus</italic> , and <italic>Salmonella enterica</italic> satisfied these criteria and were reanalyzed using a standardized computational workflow. Differential expression, comparative pathway enrichment, transcriptional signature, and gene set enrichment analyses were integrated to distinguish conserved from pathogen-specific host responses. Despite marked differences in gene expression, all four bacterial infections converged on conserved antibacterial immune program characterized by activation of inflammatory and innate immune pathways. In contrast, transcriptional divergence primarily reflected selective remodeling of host cellular functions, including metabolism, cell-cycle regulation, extracellular matrix organization, and protein synthesis, rather than differences in immune activation itself. Although overlap in differentially expressed genes was limited, pathway-level analyses revealed strong functional convergence, demonstrating that macrophage antibacterial immunity is organized around a conserved functional architecture overlaid by pathogen-specific transcriptional remodeling. Our findings support hierarchical organization of macrophage antibacterial immunity comprising a conserved inflammatory core and a pathogen-specific layer of functional remodeling. This systems-level framework extends beyond pathogen-centric transcriptomics, providing a foundation for comparative host-pathogen studies and for identifying both broadly conserved and pathogen-specific targets for host-directed antibacterial therapies. </p>