Journal article
Paralogous Outer Membrane Proteins Mediate Uptake of Different Forms of Iron and Synergistically Govern Virulence in Francisella tularensis tularensis
The Journal of biological chemistry, v 287(30), pp 25191-25202
20 Jul 2012
PMID: 22661710
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Background:
FslE and FupA are
Francisella
-specific paralogous proteins involved in iron acquisition.
Results:
fslE
mutation disrupts siderophore-mediated ferric iron uptake,
fupA
mutation impairs high affinity ferrous iron uptake, and both mutations impact virulence.
Conclusion:
Optimal iron acquisition and virulence require both paralogs.
Significance:
Iron acquisition mechanisms are potential targets for preventive or therapeutic intervention in
F. tularensis
infections.
Francisella tularensis
subsp.
tularensis
is a highly infectious bacterium causing acute disease in mammalian hosts. Mechanisms for the acquisition of iron within the iron-limiting host environment are likely to be critical for survival of this intracellular pathogen. FslE (FTT0025) and FupA (FTT0918) are paralogous proteins that are predicted to form β-barrels in the outer membrane of virulent strain Schu S4 and are unique to
Francisella
species. Previous studies have implicated both FupA, initially identified as a virulence factor and FslE, encoded by the siderophore biosynthetic operon, in iron acquisition. Using single and double mutants, we demonstrated that these paralogs function in concert to promote growth under iron limitation. We used a
55
Fe transport assay to demonstrate that FslE is involved in siderophore-mediated ferric iron uptake, whereas FupA facilitates high affinity ferrous iron uptake. Optimal replication within J774A.1 macrophage-like cells required at least one of these uptake systems to be functional. In a mouse model of tularemia, the Δ
fupA
mutant was attenuated, but the Δ
fslE
Δ
fupA
mutant was significantly more attenuated, implying that the two systems of iron acquisition function synergistically to promote virulence. These studies highlight the importance of specific iron acquisition functions, particularly that of ferrous iron, for virulence of
F. tularensis
in the mammalian host.
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Details
- Title
- Paralogous Outer Membrane Proteins Mediate Uptake of Different Forms of Iron and Synergistically Govern Virulence in Francisella tularensis tularensis
- Creators
- Girija Ramakrishnan - University of VirginiaBhaswati Sen - University of VirginiaRichard Johnson - University of Virginia
- Publication Details
- The Journal of biological chemistry, v 287(30), pp 25191-25202
- Publisher
- American Society for Biochemistry and Molecular Biology
- Grant note
- AI067823 / National Institutes of Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine
- Web of Science ID
- WOS:000306651700029
- Scopus ID
- 2-s2.0-84864113215
- Other Identifier
- 991021448026804721
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- Web of Science research areas
- Biochemistry & Molecular Biology