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Article https://doi.org/10.1038/s41467-025-57331-6Transcriptional diversif i cation in a human-adapting zoonotic pathogen drives niche-specif i c evolutionSoma Ghosh1,7 , Chao-Jung Wu 1,4,7 , Abraham G. Moller 1 , Adrien Launay 1,5 ,Laina N. Hall2,6 , Bryan T. Hansen 2 , Elizabeth R. Fischer 2 , Jung-Ho Youn 3 ,Pavel P. Khil1,3& John P. Dekker1,3Bacterial pathogens can undergo striking adaptive evolutionary change in thecontext of infection, driven by selection forces associated with host defensesandantibiotictreatment.Inthiswork,weanalyzethetranscriptionallandscapeassociated with adaptation in an emerging zoonotic pathogen, Bordetellahinzii, as it evolved during a 45-month infection in an IL12Rβ1-def i cientimmunocompromised host. We f i nd evidence of multiple niche-specif i c mod-if i cationsintheintravascularandgastrointestinalcompartments,involvingthesuperoxide dismutase system, glutamate and ectoine metabolism, chaperone-mediatedproteinfolding,pilusorganization,andpeptidetransport. Individualblood lineages displayed modif i cations in glutathione, phenylacetate, and3-phenylpropionatemetabolism,ironclusterassembly,andelectrontransport,whereas individual gastrointestinal lineages demonstrated changes relating togluconeogenesis, de novo pyrimidine synthesis, and transport of peptides andphosphate ions. Down regulation of the f l agellar operon with correspondingloss of f l agellar structures occurred in multiple lineages, suggesting an evolu-tionary tradeoff between motility and host immune evasion. Finally, methy-lome analysis demonstrates alteration of global genome methylationassociatedwithlossofaTypeIIImethyltransferase.Ourf i ndingsrevealstrikingplasticity in how pathogen transcriptomes explore functional space as theyevolveinthecontextofhostinfection,anddemonstratethatsuchanalysismayuncover phenotypic adaptations not apparent from genomic analysis alone.Muchworkoverthepastdecadehasfocusedonhowpathogensevolveinthecontextofcolonizationandinfectioninhumanhosts 1–5 .Avarietyof mutations associated with host adaptation and the evolution ofantimicrobial resistance have been identif i ed through genomicanalysis of clinical isolates. Less well understood is how many of themutations identif i ed in these studies alter gene expression, and whiletranscription has been studied extensively in lab strains of bacteria,remarkablylittleis known abouttranscriptomesin clinical isolates andReceived: 18 June 2024Accepted: 14 February 2025Check for updates1 Bacterial Pathogenesis and Antimicrobial Resistance Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infec-tious Diseases, National Institutes of Health, Bethesda, MD, USA.2 Research Technologies Branch, Rocky Mountain Laboratories, National Institute of AllergyandInfectiousDiseases,NationalInstitutesofHealth,Hamilton,MT,USA. 3 NationalInstitutesofHealthClinicalCenter,NationalInstitutesofHealth,Bethesda,MD,USA. 4 Presentaddress:SchoolofMedicalLaboratoryScienceandBiotechnology,CollegeofMedicalScienceandTechnology,TaipeiMedicalUniversity,Taipei 110301, Taiwan.5 Present address: Endogenomiks, Zapopan, Jalisco, Mexico. 6 Present address: University of California Berkeley, Berkeley, CA, USA.7 These authors contributed equally: Soma Ghosh, Chao-Jung Wu.e-mail: john.dekker@nih.govNature Communications| (2025) 16:2067 11234567890():,;1234567890():,;