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Here, we establish an epidemiology-guided\n                    <jats:italic>in vitro<\/jats:italic>\n                    framework to operationalize \u2018host compatibility\u2019 as a theoretical parameter that can be approximated experimentally using macrophage infection readouts. We infected two widely used but biologically distinct models, human THP-1-derived macrophages (THP-1m) and bovine macrophages (BoMac), with four MTBC human and animal strains. We quantified infected-cell frequency, intracellular bacterial burden dynamics, cell death and host transcriptome by RNA-seq. Across both models, infection phenotypes were concordant with the\n                    <jats:italic>a priori<\/jats:italic>\n                    epidemiology-informed reference pairings: the most compatible strain showed a higher late intracellular bacterial burden in its respective host, and the corresponding transcriptomes were enriched for replication, repair and cell-cycle signatures, whereas the opposite pairings showed lower bacterial burdens and stronger enrichment for endosomal, antigen-presentation and immune-signalling pathways in each cell type. Given the role of phospholipase C and virulence, we assessed\n                    <jats:italic>plc<\/jats:italic>\n                    expression and performed pharmacological inhibition experiments. These analyses revealed lineage- and macrophage-context-dependent expression patterns and reduced intracellular burden and cytotoxicity in THP-1m but not in BoMac. This framework links MTBC strain diversity to macrophage infection phenotypes and prioritizes candidate pathways potentially involved in bacterial\u2013host interactions.\n                  <\/jats:p>","DOI":"10.1099\/mgen.0.001826","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:16:17Z","timestamp":1790176577000},"source":"Crossref","is-referenced-by-count":0,"title":["Host\u2013strain compatibility shapes host transcriptional responses in macrophage in vitro infection models of Mycobacterium tuberculosis"],"prefix":"10.1099","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0727-5974","authenticated-orcid":false,"given":"Paula","family":"Ruiz-Rodriguez","sequence":"first","affiliation":[{"name":"Institute for Integrative Systems Biology (ISysBio), University of Valencia-CSIC, FISABIO Joint Research Unit Infection and Public Health, Valencia, 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