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This adaptation is often achieved by altering gene expression through two-component regulatory systems (TCSs). In Gram-negative bacteria, the response to environmental changes in osmolarity and pH is primarily mediated by the EnvZ\/OmpR TCS. Although the functioning of EnvZ\/OmpR has been well characterized in\n            <jats:italic>Escherichia coli<\/jats:italic>\n            ,\n            <jats:italic>Salmonella enterica<\/jats:italic>\n            , and the\n            <jats:italic>Yersinia<\/jats:italic>\n            genus, the importance of EnvZ\/OmpR TCS in the opportunistic human pathogen\n            <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n            has been limitedly studied. Here, we investigated the importance of EnvZ\/OmpR in\n            <jats:italic>K. pneumoniae<\/jats:italic>\n            for fitness, gene regulation, virulence, and infection. Through the generation of a markerless\n            <jats:italic>ompR<\/jats:italic>\n            -deletion mutant, we show that overall fitness of\n            <jats:italic>K. pneumoniae<\/jats:italic>\n            is not impacted\n            <jats:italic>in vitro<\/jats:italic>\n            . Using dual RNA sequencing of\n            <jats:italic>K. pneumoniae<\/jats:italic>\n            co-incubated with human lung epithelial cells, we demonstrate that the\n            <jats:italic>K. pneumoniae<\/jats:italic>\n            OmpR regulon includes important virulence factors but shows otherwise limited overlap with the regulons of other Gram-negative bacteria. In addition, we show that deletion of\n            <jats:italic>ompR<\/jats:italic>\n            in\n            <jats:italic>K. pneumoniae<\/jats:italic>\n            leads to a stronger antibacterial transcriptional response in human lung epithelial cells. Lastly, we show that OmpR is crucial for\n            <jats:italic>K. pneumoniae<\/jats:italic>\n            virulence and infection through a murine lung infection model. As the adaptation of commensal bacteria to specific niches is mediated by TCSs, we show that EnvZ\/OmpR plays a crucial role in successful lung infection, as well as in virulence. These results suggest that OmpR is an interesting target for anti-virulence drug discovery programs.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Bacteria use two-component regulatory systems (TCSs) to adapt to changes in their environment by changing their gene expression. In this study, we show that the EnvZ\/OmpR TCS of the clinically relevant opportunistic pathogen\n              <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n              plays an important role in successfully establishing lung infection and virulence. In addition, we elucidate the\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              OmpR regulon within the host. This work suggests that\n              <jats:italic>K. pneumoniae<\/jats:italic>\n              OmpR might be a promising target for innovative anti-infectives.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03966-23","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T13:39:51Z","timestamp":1702647591000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["<i>Klebsiella pneumoniae<\/i>\n            OmpR facilitates lung infection through transcriptional regulation of key virulence factors"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9865-447X","authenticated-orcid":false,"given":"Axel B.","family":"Janssen","sequence":"first","affiliation":[{"name":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1019-3558","authenticated-orcid":false,"given":"Vincent","family":"de Bakker","sequence":"additional","affiliation":[{"name":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2479-7352","authenticated-orcid":false,"given":"Rieza","family":"Aprianto","sequence":"additional","affiliation":[{"name":"Molecular Genetics Group, University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, Centre for Synthetic Biology , Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8961-1371","authenticated-orcid":false,"given":"Vincent","family":"Trebosc","sequence":"additional","affiliation":[{"name":"BioVersys AG , Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kemmer","sequence":"additional","affiliation":[{"name":"BioVersys AG , Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7896-254X","authenticated-orcid":false,"given":"Michel","family":"Pieren","sequence":"additional","affiliation":[{"name":"BioVersys AG , Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3162-6634","authenticated-orcid":false,"given":"Jan-Willem","family":"Veening","sequence":"additional","affiliation":[{"name":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne , Lausanne, 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