Two parallel pathways for ferric and ferrous iron acquisition support growth and virulence of the intracellular pathogen <i>Francisella tularensis</i> Schu S4

Pérez, Natalie; Johnson, R. Jeremy; Sen, Bhaswati; Ramakrishnan, Girija

doi:10.1002/mbo3.342

Cited by 25 publications

(25 citation statements)

References 56 publications

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“…Several recent studies have shown that fungal nutrient and element acquisition pathways may be critical for pathogenicity of both plant and human pathogens [40,41]. For example, all living organisms utilize Cu as cofactor of enzymes functioning in many cellular biochemical processes [3].…”

Section: Discussionmentioning

confidence: 99%

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

et al. 2018

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The ubiquitous fungus Aspergillus flavus is notorious for contaminating many important crops and food-stuffs with the carcinogenic mycotoxin, aflatoxin. This fungus is also the second most frequent Aspergillus pathogen after A. fumigatus infecting immunosuppressed patients. In many human fungal pathogens including A. fumigatus, the ability to defend from toxic levels of copper (Cu) is essential in pathogenesis. In A. fumigatus, the Cu-fist DNA binding protein, AceA, and the Cu ATPase transporter, CrpA, play critical roles in Cu defense. Here, we show that A. flavus tolerates higher concentrations of Cu than A. fumigatus and other Aspergillus spp. associated with the presence of two homologs of A. fumigatus CrpA termed CrpA and CrpB. Both crpA and crpB are transcriptionally induced by increasing Cu concentrations via AceA activity. Deletion of crpA or crpB alone did not alter high Cu tolerance, suggesting they are redundant. Deletion of both genes resulted in extreme Cu sensitivity that was greater than that following deletion of the regulatory transcription factor aceA. The ΔcrpAΔcrpB and ΔaceA strains were also sensitive to ROI stress. Compared to wild type, these mutants were impaired in the ability to colonize maize seed treated with Cu fungicide but showed no difference in virulence on non-treated seed. A mouse model of invasive aspergillosis showed ΔcrpAΔcrpB and to a lesser degree ΔaceA to be significantly reduced in virulence, following the greater sensitivity of ΔcrpAΔcrpB to Cu than ΔaceA.

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Section: Discussionmentioning

confidence: 99%

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

et al. 2018

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“…Additionally, detection of siderophore activity in culture supernatants of an LVS Δ fslA-F mutant required complementation with the fslB gene in addition to the biosynthetic genes fslA and fslC (Pérez et al, 2016). These observations support a role for FslB in export of the siderophore across the cytoplasmic membrane.…”

Section: Introductionmentioning

confidence: 99%

“…The role of this protein in siderophore-mediated iron uptake across the cytoplasmic membrane was deduced on the basis of complementation studies: a Schu S4 Δ fslA-F mutant is able to transport 55 Fe 3+ complexed to siderophore only when complemented with the fslD gene in addition to the fslE receptor gene (see below; Pérez et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

“…In transport assays, fslE mutants proved incapable of siderophore-mediated 55 Fe 3+ uptake, establishing a role for FslE as receptor for the siderophore (Ramakrishnan et al, 2012). FslE can also transport the iron mimic gallium in complex with rhizoferrin as shown by the resistance of fslA and fslE mutants to gallium (Pérez et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

“…Studies with a Δ fslF mutant in Schu S4 indicate that the gene does not influence iron transport in F. tularensis (Pérez et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Iron and Virulence in Francisella tularensis

Ramakrishnan

2017

Front. Cell. Infect. Microbiol.

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Francisella tularensis, the causative agent of tularemia, is a Gram-negative bacterium that infects a variety of cell types including macrophages, and propagates with great efficiency in the cytoplasm. Iron, essential for key enzymatic and redox reactions, is among the nutrients required to support this pathogenic lifestyle and the bacterium relies on specialized mechanisms to acquire iron within the host environment. Two distinct pathways for iron acquisition are encoded by the F. tularensis genome- a siderophore-dependent ferric iron uptake system and a ferrous iron transport system. Genes of the Fur-regulated fslABCDEF operon direct the production and transport of the siderophore rhizoferrin. Siderophore biosynthesis involves enzymes FslA and FslC, while export across the inner membrane is mediated by FslB. Uptake of the rhizoferrin- ferric iron complex is effected by the siderophore receptor FslE in the outer membrane in a TonB-independent process, and FslD is responsible for uptake across the inner membrane. Ferrous iron uptake relies largely on high affinity transport by FupA in the outer membrane, while the Fur-regulated FeoB protein mediates transport across the inner membrane. FslE and FupA are paralogous proteins, sharing sequence similarity and possibly sharing structural features as well. This review summarizes current knowledge of iron acquisition in this organism and the critical role of these uptake systems in bacterial pathogenicity.

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Iron Acquisition by Bacterial Pathogens: Beyond Tris‐Catecholate Complexes

2020

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Sequestration of the essential nutrient iron from bacterial invaders that colonize the vertebrate host is a central feature of nutritional immunity and the “fight over transition metals” at the host‐pathogen interface. The iron quota for many bacterial pathogens is large, as iron enzymes often make up a significant share of the metalloproteome. Iron enzymes play critical roles in respiration, energy metabolism, and other cellular processes by catalyzing a wide range of oxidation‐reduction, electron transfer, and oxygen activation reactions. In this Concept article, we discuss recent insights into the diverse ways that bacterial pathogens acquire this essential nutrient, beyond the well‐characterized tris‐catecholate FeIII complexes, in competition and cooperation with significant host efforts to cripple these processes. We also discuss pathogen strategies to adapt their metabolism to less‐than‐optimal iron concentrations, and briefly speculate on what might be an integrated adaptive response to the concurrent limitation of both iron and zinc in the infected host.

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Two parallel pathways for ferric and ferrous iron acquisition support growth and virulence of the intracellular pathogen Francisella tularensis Schu S4

Cited by 25 publications

References 56 publications

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

Iron and Virulence in Francisella tularensis

Iron Acquisition by Bacterial Pathogens: Beyond Tris‐Catecholate Complexes

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