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Here we characterize the mechanisms driving adaptive evolution of the emerging zoonotic pathogen <jats:italic>Bordetella hinzii<\/jats:italic> in a patient with interleukin-12 receptor \u03b21 deficiency. Genomic sequencing of 24 <jats:italic>B. hinzii<\/jats:italic> isolates cultured from blood and stool over 45 months revealed a clonal lineage that had undergone extensive within-host genetic and phenotypic diversification. Twenty of 24 isolates shared an E9G substitution in the DNA polymerase III \u03b5-subunit active site, resulting in a proofreading deficiency. Within this proofreading-deficient clade, multiple lineages with mutations in DNA repair genes and altered mutational spectra emerged and dominated clinical cultures for more than 12 months. Multiple enzymes of the tricarboxylic acid cycle and gluconeogenesis pathways were repeatedly mutated, suggesting rapid metabolic adaptation to the human environment. Furthermore, an excess of G:C\u2009&gt;\u2009T:A transversions suggested that oxidative stress shaped genetic diversification during adaptation. We propose that inactivation of DNA proofreading activity in combination with prolonged, but sub-lethal, oxidative attack resulting from the underlying host immunodeficiency facilitated rapid genomic adaptation. These findings suggest a fundamental role for host immune phenotype in shaping pathogen evolution following zoonotic infection.<\/jats:p>","DOI":"10.1038\/s41467-021-24668-7","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T10:03:30Z","timestamp":1627034610000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["In vivo evolution of an emerging zoonotic bacterial pathogen in an immunocompromised human host"],"prefix":"10.1038","volume":"12","author":[{"given":"A.","family":"Launay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.-J.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8040-9620","authenticated-orcid":false,"given":"A.","family":"Dulanto Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.-H.","family":"Youn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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