{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:59:08Z","timestamp":1790546348774,"version":"4.1.0"},"reference-count":202,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI128379, AI029735"],"award-info":[{"award-number":["AI128379, AI029735"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Connecticut Children\u2019s Medical Center"},{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel","doi-asserted-by":"crossref","award":["88887.338735\/2019-00"],"award-info":[{"award-number":["88887.338735\/2019-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fondation Etch\u00e8bes-Fondation de France","award":["(S-CM16008)"],"award-info":[{"award-number":["(S-CM16008)"]}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"crossref","award":["No 665807"],"award-info":[{"award-number":["No 665807"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Leptospira interrogans<\/jats:italic>\n                    , the causative agent of most cases of human leptospirosis, must respond to myriad environmental signals during its free-living and pathogenic lifestyles. Previously, we compared\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>interrogans<\/jats:italic>\n                    cultivated\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a dialysis membrane chamber (DMC) peritoneal implant model. From these studies emerged the importance of genes encoding the Peroxide responsive regulators PerRA and PerRB. First described in in\n                    <jats:italic>Bacillus subtilis<\/jats:italic>\n                    , PerRs are widespread in Gram-negative and -positive bacteria, where regulate the expression of gene products involved in detoxification of reactive oxygen species and virulence. Using\n                    <jats:italic>perRA<\/jats:italic>\n                    and\n                    <jats:italic>perRB<\/jats:italic>\n                    single and double mutants, we establish that\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>interrogans<\/jats:italic>\n                    requires at least one functional PerR for infectivity and renal colonization in a reservoir host. Our finding that the\n                    <jats:italic>perRA<\/jats:italic>\n                    \/\n                    <jats:italic>B<\/jats:italic>\n                    double mutant survives at wild-type levels in DMCs is noteworthy as it demonstrates that the loss of virulence is not due to a metabolic lesion (\n                    <jats:italic>i<\/jats:italic>\n                    .\n                    <jats:italic>e<\/jats:italic>\n                    ., metal starvation) but instead reflects dysregulation of virulence-related gene products. Comparative RNA-Seq analyses of\n                    <jats:italic>perRA<\/jats:italic>\n                    ,\n                    <jats:italic>perRB<\/jats:italic>\n                    and\n                    <jats:italic>perRA\/B<\/jats:italic>\n                    mutants cultivated within DMCs identified 106 genes that are dysregulated in the double mutant, including\n                    <jats:italic>ligA<\/jats:italic>\n                    ,\n                    <jats:italic>ligB<\/jats:italic>\n                    and\n                    <jats:italic>lvrA\/B<\/jats:italic>\n                    sensory histidine kinases. Decreased expression of LigA and LigB in the\n                    <jats:italic>perRA<\/jats:italic>\n                    \/\n                    <jats:italic>B<\/jats:italic>\n                    mutant was not due to loss of LvrAB signaling. The majority of genes in the\n                    <jats:italic>perRA<\/jats:italic>\n                    and\n                    <jats:italic>perRB<\/jats:italic>\n                    single and double mutant DMC regulons were differentially expressed only\n                    <jats:italic>in vivo<\/jats:italic>\n                    , highlighting the importance of host signals for regulating gene expression in\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>interrogans<\/jats:italic>\n                    . Importantly, the PerRA, PerRB and PerRA\/B DMC regulons each contain multiple genes related to environmental sensing and\/or transcriptional regulation. Collectively, our data suggest that PerRA and PerRB are part of a complex regulatory network that promotes host adaptation by\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>interrogans<\/jats:italic>\n                    within mammals.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009078","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T13:44:59Z","timestamp":1638452699000},"page":"e1009078","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence of Leptospira interrogans"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-2165","authenticated-orcid":true,"given":"Andr\u00e9 A.","family":"Grassmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crispin","family":"Zavala-Alvarado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5095-2198","authenticated-orcid":true,"given":"Everton B.","family":"Bettin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5338-5579","authenticated-orcid":true,"given":"Mathieu","family":"Picardeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Benaroudj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1170-4102","authenticated-orcid":true,"given":"Melissa J.","family":"Caimano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"issue":"2","key":"ppat.1009078.ref001","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1128\/CMR.14.2.296-326.2001","article-title":"Leptospirosis","volume":"14","author":"PN Levett","year":"2001","journal-title":"Clin Microbiol Rev"},{"issue":"4","key":"ppat.1009078.ref002","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ijid.2007.09.011","article-title":"The globalization of leptospirosis: worldwide incidence trends","volume":"12","author":"G Pappas","year":"2008","journal-title":"Int J Infect Dis"},{"issue":"9","key":"ppat.1009078.ref003","doi-asserted-by":"crossref","first-page":"e0003898","DOI":"10.1371\/journal.pntd.0003898","article-title":"Global morbidity and mortality of Leptospirosis: A systematic review.","volume":"9","author":"F Costa","year":"2015","journal-title":"PLoS Negl Trop Dis"},{"issue":"5","key":"ppat.1009078.ref004","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1097\/01.qco.0000178824.05715.2c","article-title":"Leptospirosis","volume":"18","author":"AJ McBride","year":"2005","journal-title":"Curr Opin Infect Dis"},{"key":"ppat.1009078.ref005","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1472-698X-7-2","article-title":"Slum health: diseases of neglected populations.","volume":"7","author":"LW Riley","year":"2007","journal-title":"BMC Int Health Hum Rights"},{"issue":"2","key":"ppat.1009078.ref006","doi-asserted-by":"crossref","first-page":"e0004403","DOI":"10.1371\/journal.pntd.0004403","article-title":"What makes a bacterial species pathogenic?:Comparative genomic analysis of the genus Leptospira.","volume":"10","author":"DE Fouts","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"issue":"3","key":"ppat.1009078.ref007","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0749-0720(15)30532-6","article-title":"Leptospirosis as a cause of reproductive failure.","volume":"10","author":"WA Ellis","year":"1994","journal-title":"Vet Clin North Am Food Anim Pract"},{"issue":"3","key":"ppat.1009078.ref008","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.theriogenology.2006.04.016","article-title":"Reproductive losses caused by bovine viral diarrhea virus and leptospirosis","volume":"66","author":"DL Grooms","year":"2006","journal-title":"Theriogenology"},{"issue":"3\u20134","key":"ppat.1009078.ref009","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.vetmic.2009.03.012","article-title":"de la Pena Moctezuma A. 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