title: Two parallel pathways for ferric and ferrous iron acquisition support growth and virulence of the intracellular pathogen Francisella tularensis Schu S4.
abstract: Iron acquisition mechanisms in Francisella tularensis, the causative agent of tularemia, include the Francisella siderophore locus (fsl) siderophore operon and a ferrous iron-transport system comprising outer-membrane protein FupA and inner-membrane transporter FeoB. To characterize these mechanisms and to identify any additional iron uptake systems in the virulent subspecies tularensis, single and double deletions were generated in the fsl and feo iron acquisition systems of the strain Schu S4. Deletion of the entire fsl operon caused loss of siderophore production that could be restored by complementation with the biosynthetic genes fslA and fslC and Major Facilitator Superfamily (MFS) transporter gene fslB. (55) Fe-transport assays demonstrated that siderophore-iron uptake required the receptor FslE and MFS transporter FslD. A ΔfeoB' mutation resulted in loss of ability to transport ferrous iron ((55) Fe(2+) ). A ΔfeoB' ΔfslA 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 fsl and feo pathways function independently and operate in parallel to effectively support virulence of F. tularensis.
authors.affiliation: Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Natalie
authors.initials: N
authors.lastname: Pérez
authors.affiliation: Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Richard
authors.initials: R
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Sen
authors.affiliation: Department of Medicine, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, 22908.
authors.forename: Girija
authors.identifier: 0000-0002-9543-3583
authors.initials: G
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D005290:Ferric Compounds / Q000378:metabolism*; D005296:Ferrous Compounds / Q000378:metabolism*; D005604:Francisella tularensis / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D017353:Gene Deletion; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018977:Micronutrients / Q000378:metabolism; D017262:Siderophores / Q000235:genetics / Q000378:metabolism; D014406:Tularemia / Q000382:microbiology / Q000473:pathology
chemical_list: D027682:Cation Transport Proteins; D005290:Ferric Compounds; D005296:Ferrous Compounds; D018977:Micronutrients; D017262:Siderophores; D003300:Copper; D007501:Iron
keywords: Copper; FeoB; gallium; membrane transport; siderophore.