{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:24:20Z","timestamp":1781245460041,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009604","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000}}],"reference-count":110,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Burkholderia pseudomallei<\/jats:italic>, the etiological agent of melioidosis in humans and animals, often occupies environmental niches and infection sites characterized by limited concentrations of oxygen. Versatile genomic features enable this pathogen to maintain its physiology and virulence under hypoxia, but the crucial regulatory networks employed to switch from oxygen dependent respiration to alternative terminal electron acceptors (TEA) like nitrate, remains poorly understood. Here, we combined a Tn<jats:italic>5<\/jats:italic> transposon mutagenesis screen and an anaerobic growth screen to identify a two-component signal transduction system with homology to RegAB. We show that RegAB is not only essential for anaerobic growth, but also for full virulence in cell lines and a mouse infection model. Further investigations of the RegAB regulon, using a global transcriptomic approach, identified 20 additional regulators under transcriptional control of RegAB, indicating a superordinate role of RegAB in the <jats:italic>B<\/jats:italic>. <jats:italic>pseudomallei<\/jats:italic> anaerobiosis regulatory network. Of the 20 identified regulators, NarX\/L and a FNR homolog were selected for further analyses and a role in adaptation to anaerobic conditions was demonstrated. Growth experiments identified nitrate and intermediates of the denitrification process as the likely signal activateing RegAB, NarX\/L, and probably of the downstream regulators Dnr or NsrR homologs. While deletions of individual genes involved in the denitrification process demonstrated their important role in anaerobic fitness, they showed no effect on virulence. This further highlights the central role of RegAB as the master regulator of anaerobic metabolism in <jats:italic>B<\/jats:italic>. <jats:italic>pseudomallei<\/jats:italic> and that the complete RegAB-mediated response is required to achieve full virulence. In summary, our analysis of the RegAB-dependent modulon and its interconnected regulons revealed a key role for RegAB of <jats:italic>B<\/jats:italic>. <jats:italic>pseudomallei<\/jats:italic> in the coordination of the response to hypoxic conditions and virulence, in the environment and the host.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009604","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T19:58:59Z","timestamp":1622231939000},"page":"e1009604","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["RegAB Homolog of Burkholderia pseudomallei is the Master Regulator of Redox Control and involved in Virulence"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-6162","authenticated-orcid":true,"given":"Julia","family":"Phenn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-2568","authenticated-orcid":true,"given":"Jan","family":"Pan\u00e9-Farr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1123-1053","authenticated-orcid":true,"given":"Nikolai","family":"Meukow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0690-8998","authenticated-orcid":true,"given":"Annelie","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4398-1465","authenticated-orcid":true,"given":"Anne","family":"Troitzsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5704-3955","authenticated-orcid":true,"given":"Gabriel E.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5668-7786","authenticated-orcid":true,"given":"Sabine","family":"Lichtenegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Steinmetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3921-6776","authenticated-orcid":true,"given":"Christian","family":"Kohler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"ppat.1009604.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2911(01)44010-0","article-title":"Functional versatility in the CRP-FNR superfamily of transcription factors: FNR and FLP","volume":"44","author":"J Green","year":"2001","journal-title":"Adv Microb Physiol"},{"key":"ppat.1009604.ref002","article-title":"Redox-sensing iron-sulfur cluster regulators","author":"JC Crack","year":"2017","journal-title":"Antioxid Redox Signal"},{"issue":"2","key":"ppat.1009604.ref003","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S1369-5274(99)80034-4","article-title":"Carbon catabolite repression in bacteria","volume":"2","author":"J Stulke","year":"1999","journal-title":"Curr Opin Microbiol"},{"issue":"1\u20133","key":"ppat.1009604.ref004","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/BF00871630","article-title":"The FNR family of transcriptional regulators","volume":"66","author":"S. 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Wu","year":"2010","journal-title":"MBio"},{"issue":"10","key":"ppat.1009604.ref032","first-page":"e000081","article-title":"The RegA regulon exhibits variability in response to altered growth conditions and differs markedly between Rhodobacter species","volume":"2","author":"HS Schindel","year":"2016","journal-title":"Microb Genom"},{"issue":"18","key":"ppat.1009604.ref033","doi-asserted-by":"crossref","DOI":"10.1128\/JB.00156-18","article-title":"The Mla Pathway Plays an Essential Role in the Intrinsic Resistance of Burkholderia cepacia Complex Species to Antimicrobials and Host Innate Components","volume":"200","author":"SP Bernier","year":"2018","journal-title":"J Bacteriol"},{"issue":"5","key":"ppat.1009604.ref034","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1093\/nar\/29.5.1097","article-title":"Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis 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