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The\n                    <jats:italic>ramR<\/jats:italic>\n                    \u2010\n                    <jats:italic>ramA<\/jats:italic>\n                    regulatory system critically influences drug resistance by regulating the AcrAB\u2010TolC efflux pump, which also plays a crucial role in the pathogenicity of\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    . However, the mechanism of the\n                    <jats:italic>ramR<\/jats:italic>\n                    \u2010\n                    <jats:italic>ramA<\/jats:italic>\n                    system on bacteria\u2010host interaction remains unclear. To determine how specific mutations in\n                    <jats:italic>ramR<\/jats:italic>\n                    influence eravacycline (ERV) resistance and their impact on the immune activation capabilities of\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    , thereby highlighting potential targets for therapeutic intervention, we performed genetic sequencing to identify mutations in\n                    <jats:italic>ramR<\/jats:italic>\n                    . Then, the CRISPR\u2010Cas9 technology was employed to construct specific\n                    <jats:italic>ramR<\/jats:italic>\n                    mutations into\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    , which were then subjected to phenotypic and functional assays in both in vitro and in vivo (mouse models, macrophage, and blood\u2010killing experiment) settings.\n                    <jats:italic>ramR<\/jats:italic>\n                    L58P and F165L genetic alterations disrupt the binding affinity of RamR to the\n                    <jats:italic>ramA<\/jats:italic>\n                    promoter, thereby upregulating the efflux pump expression and increasing ERV minimum inhibitory concentration values up to 64\u2010fold compared to the wild\u2010type. Concurrently, these mutations modulate lipid A structure by increasing 2\u2010hydroxy fatty acid chain abundance. In mouse models,\n                    <jats:italic>ramR<\/jats:italic>\n                    L58P and F165L mutants showed lower bacterial burden in organs (spleen, lung, and kidney) 6\u2009h post\u2010infection, and are fast cleared in 48\u2009h. Furthermore, despite lower intracellular bacterial loads,\n                    <jats:italic>ramR<\/jats:italic>\n                    L58P and F165L mutants induce heightened pro\u2010inflammatory cytokine responses in macrophages and elevate systemic cytokine levels (interleukin [IL]2, IL4, IL6, IL12, interferon\u2010\u03b1, and interferon\u2010\u03b3) in human blood co\u2010culture experiments. This study illuminates the critical role of\n                    <jats:italic>ramR<\/jats:italic>\n                    mutations in conferring ERV resistance and enhancing immune responses in\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    . The dual impact of these mutations on both antimicrobial resistance and immune activation not only underscores the challenges in treating infections but also advocates for heightened surveillance and innovative strategies to counteract the emerging threat of antimicrobial\u2010resistant\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/imo2.39","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T22:39:36Z","timestamp":1731191976000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dual role of\n                    <i>ramR<\/i>\n                    mutation in enhancing immune activation and elevating eravacycline resistance in\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1002","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1501-7980","authenticated-orcid":false,"given":"Wei","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"},{"name":"Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyao","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 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