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To characterize these mechanisms and to identify any additional iron uptake systems in the virulent subspecies <jats:italic>tularensis<\/jats:italic>, single and double deletions were generated in the <jats:italic>fsl<\/jats:italic> and <jats:italic>feo<\/jats:italic> iron acquisition systems of the strain Schu S4. Deletion of the entire <jats:italic>fsl<\/jats:italic> operon caused loss of siderophore production that could be restored by complementation with the biosynthetic genes <jats:italic>fslA<\/jats:italic> and <jats:italic>fslC<\/jats:italic> and Major Facilitator Superfamily (<jats:styled-content style=\"fixed-case\">MFS<\/jats:styled-content>) transporter gene <jats:italic>fslB<\/jats:italic>. <jats:sup>55<\/jats:sup>Fe\u2010transport assays demonstrated that siderophore\u2010iron uptake required the receptor FslE and <jats:styled-content style=\"fixed-case\">MFS<\/jats:styled-content> transporter FslD. A \u0394<jats:italic>feoB<\/jats:italic>\u2032 mutation resulted in loss of ability to transport ferrous iron (<jats:sup>55<\/jats:sup>Fe<jats:sup>2+<\/jats:sup>). A \u0394<jats:italic>feoB<\/jats:italic>\u2032 \u0394<jats:italic>fslA<\/jats:italic> mutant that required added exogenous siderophore for growth in vitro was unable to grow within tissue culture cells and was avirulent in mice, indicating that no compensatory cryptic iron uptake systems were induced in vivo. These studies demonstrate that the <jats:italic>fsl<\/jats:italic> and <jats:italic>feo<\/jats:italic> pathways function independently and operate in parallel to effectively support virulence of <jats:italic>F.\u00a0tularensis<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/mbo3.342","type":"journal-article","created":{"date-parts":[[2016,2,26]],"date-time":"2016-02-26T10:57:06Z","timestamp":1456484226000},"page":"453-468","source":"Crossref","is-referenced-by-count":24,"title":["Two parallel pathways for ferric and ferrous iron acquisition support growth and virulence of the intracellular pathogen <i>Francisella tularensis<\/i> Schu S4"],"prefix":"10.1002","volume":"5","author":[{"given":"Natalie","family":"P\u00e9rez","sequence":"first","affiliation":[{"name":"Department of Medicine Division of Infectious Diseases and International Health University of Virginia  Charlottesville Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Infectious Diseases and International Health University of Virginia  Charlottesville Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaswati","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Infectious Diseases and International Health University of Virginia  Charlottesville Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9543-3583","authenticated-orcid":false,"given":"Girija","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Infectious Diseases and International Health University of Virginia  Charlottesville Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12138"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-5-29"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh417"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02882-07"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00808-15"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/ic960526d"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00144624"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a010314"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.13.2.232-235.1965"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.055533-0"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10534-010-9361-x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10534-008-9170-7"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/genomeA.00941-14"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01975-05"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-5561-1_8"},{"key":"e_1_2_7_17_1","first-page":"935","article-title":"Siderophore\u2010mediated mechanism of gallium uptake demonstrated in the microorganism ustilago sphaerogena","volume":"21","author":"Emery T.","year":"1980","journal-title":"Clin. 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