Cell-surface signaling in<i>Pseudomonas</i>: stress responses, iron transport, and pathogenicity

Llamas, María A.; Imperi, Francesco; Visca, Paolo; Lamont, Iain L.

doi:10.1111/1574-6976.12078

Cited by 149 publications

(224 citation statements)

References 211 publications

(354 reference statements)

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“…While P. aeruginosa PAO1 carries three different tonB genes (tonB1, tonB2, and tonB3), tonB1 has been demonstrated to play the main role in siderophore-mediated iron uptake (17)(18)(19). Additionally, the P. aeruginosa genome encodes more than 30 TonBdependent outer membrane receptors, some of which are implicated in the uptake of xenosiderophores (i.e., siderophores produced by other microorganisms, such as ferrichrome or deferoxamine) or other, still uncharacterized exogenous iron carriers (20,21). In addition to TonB-dependent iron uptake systems, P. aeruginosa has the ability to acquire ferrous iron (Fe 2ϩ ) via the TonB-independent Feo system, whose main component is the FeoB permease, located in the cytoplasmic membrane and containing a cytosolic N-terminal domain with GTPase activity (22).…”

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“…Most of the P. aeruginosa iron uptake systems have a second level of regulation, resulting from autoinduction of iron uptake genes, which takes place when the iron carrier is effectively internalized by the cell (8,21,24). The best-studied autoregulatory system is the pyoverdine surface signaling cascade, in which ferripyoverdine binding to the FpvA receptor transmits a signal to the cytoplasm via the membrane-bound anti-sigma factor protein FpvR, which ultimately results in activation of both the FpvI and PvdS sigma factors.…”

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“…These include pyoverdine biosynthetic genes as well as genes encoding major P. aeruginosa virulence factors, such as the PrpL protease and exotoxin A (25,26). Thus, pyoverdine is predicted to have dual roles in P. aeruginosa virulence: (i) it provides bacteria with an essential nutrient for in vivo growth and (ii) it serves as a signal molecule for the expression of major virulence factors, which in turn may contribute to increased iron availability to bacteria during infection (21,25).…”

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Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection

et al. 2016

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Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia and chronic lung infections in cystic fibrosis patients. Iron is essential for bacterial growth, and P. aeruginosa expresses multiple iron uptake systems, whose role in lung infection deserves further investigation. P. aeruginosa Fe 3؉ uptake systems include the pyoverdine and pyochelin siderophores and two systems for heme uptake, all of which are dependent on the TonB energy transducer. P. aeruginosa also has the FeoB transporter for Fe 2؉ acquisition. To assess the roles of individual iron uptake systems in P. aeruginosa lung infection, single and double deletion mutants were generated in P. aeruginosa PAO1 and characterized in vitro, using iron-poor media and human serum, and in vivo, using a mouse model of lung infection. The iron uptake-null mutant (tonB1 feoB) and the Fe 3؉ transport mutant (tonB1) did not grow aerobically under low-iron conditions and were avirulent in the mouse model. Conversely, the wild type and the feoB, hasR phuR (heme uptake), and pchD (pyochelin) mutants grew in vitro and caused 60 to 90% mortality in mice. The pyoverdine mutant (pvdA) and the siderophore-null mutant (pvdA pchD) grew aerobically in iron-poor media but not in human serum, and they caused low mortality in mice (10 to 20%). To differentiate the roles of pyoverdine in iron uptake and virulence regulation, a pvdA fpvR double mutant defective in pyoverdine production but expressing wild-type levels of pyoverdine-regulated virulence factors was generated. Deletion of fpvR in the pvdA background partially restored the lethal phenotype, indicating that pyoverdine contributes to the pathogenesis of P. aeruginosa lung infection by combining iron transport and virulence-inducing capabilities.

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Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection

et al. 2016

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“…Fur also affects the expression of genes encoding virulence traits, including toxins and extracellular proteases (21)(22)(23). Fur regulation in P. aeruginosa mainly occurs through the regulation of cell surface signaling (CSS) systems, which are comprised of a TonB-dependent (OM) receptor, an extracytoplasmic function (ECF) sigma factor, and an anti-sigma factor that regulates the activity of the ECF sigma factor (24). As an example, Fur represses expression of pvdS, encoding an ECF sigma factor that directly activates expression of genes for pyoverdine biosynthesis and uptake, as well as multiple virulence factors (22,(25)(26)(27).…”

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The prrF -Encoded Small Regulatory RNAs Are Required for Iron Homeostasis and Virulence of Pseudomonas aeruginosa

et al. 2015

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Pseudomonas aeruginosa is an opportunistic pathogen that requires iron to cause infection, but it also must regulate the uptake of iron to avoid iron toxicity. The iron-responsive PrrF1 and PrrF2 small regulatory RNAs (sRNAs) are part of P. aeruginosa's iron regulatory network and affect the expression of at least 50 genes encoding iron-containing proteins. The genes encoding the PrrF1 and PrrF2 sRNAs are encoded in tandem in P. aeruginosa, allowing for the expression of a distinct, heme-responsive sRNA named PrrH that appears to regulate genes involved in heme metabolism. Using a combination of growth, mass spectrometry, and gene expression analysis, we showed that the ⌬prrF1,2 mutant, which lacks expression of the PrrF and PrrH sRNAs, is defective for both iron and heme homeostasis. We also identified phuS, encoding a heme binding protein involved in heme acquisition, and vreR, encoding a previously identified regulator of P. aeruginosa virulence genes, as novel targets of prrF-mediated heme regulation. Finally, we showed that the prrF locus encoding the PrrF and PrrH sRNAs is required for P. aeruginosa virulence in a murine model of acute lung infection. Moreover, we showed that inoculation with a ⌬prrF1,2 deletion mutant protects against future challenge with wild-type P. aeruginosa. Combined, these data demonstrate that the prrF-encoded sRNAs are critical regulators of P. aeruginosa virulence. Pseudomonas aeruginosa is a ubiquitous Gram-negative bacterium and versatile opportunistic pathogen. Iron is required for P. aeruginosa virulence (1-6) and is obtained through several mechanisms. In anaerobic environments, iron in its ferrous form is freely diffusible through the outer membrane (OM) and transported into the cytoplasm by the Feo inner membrane transport system (7,8). However, the insolubility of ferric iron in aerobic environments limits accessibility to this nutrient. Moreover, the sequestration of iron by host proteins creates a substantial barrier to infection (9, 10). To overcome this barrier, P. aeruginosa synthesizes and secretes two siderophores, pyoverdine and pyochelin, which scavenge ferric iron (1-4). P. aeruginosa can also acquire heme, an abundant source of iron in the human host (11). Once internalized, heme is sequestered by the cytosolic PhuS heme chaperone (12). PhuS transfers heme to the iron-regulated HemO heme oxygenase, which degrades heme to biliverdin, releasing carbon monoxide and iron (13,14). Several studies have shown that iron acquisition is essential for P. aeruginosa virulence (1-5) and biofilm formation (15-17), demonstrating the central role of this element in P. aeruginosa pathogenesis.Despite its essentiality, iron and heme can be toxic due to their ability to catalyze the formation of reactive oxygen species. Thus, to maintain iron homeostasis, P. aeruginosa must be able to not only acquire iron but also regulate uptake of iron and heme from the environment, as well as iron use and storage. Expression of genes encoding iron and heme uptake systems in P. aeruginosa is ...

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“…Production of siderophore receptors is an energetically costly process and generally only occurs when the cognate siderophore is present in the environment (1,5,6). This process is usually controlled by a trans-envelope regulatory signal transduction pathway known as cell-surface signaling (CSS) 2 (7)(8)(9). This regulatory cascade involves three proteins: the siderophore receptor itself, an anti-sigma factor located at the cytoplasmic membrane, and an extracytoplasmic function (ECF) sigma factor ( ECF ) in the cytosol.…”

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Self-cleavage of the Pseudomonas aeruginosa Cell-surface Signaling Anti-sigma Factor FoxR Occurs through an N-O Acyl Rearrangement

Bastiaansen

Ulsen

Bitter

et al. 2015

Journal of Biological Chemistry

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Background: Many transmembrane anti-sigma factors, including P. aeruginosa FoxR, undergo periplasmic self-cleavage by an unknown mechanism. Results: Presence of an OH or SH group at ϩ1 of the cleavage site is essential for FoxR self-cleavage. Conclusion: FoxR self-cleavage is mediated by an N-O acyl rearrangement. Significance: The complex proteolytic network that modulates alternative sigma factor activity in Gram-negative bacteria also includes an enzyme-independent step.

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Cell-surface signaling inPseudomonas: stress responses, iron transport, and pathogenicity

Cited by 149 publications

References 211 publications

Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection

Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection

The prrF -Encoded Small Regulatory RNAs Are Required for Iron Homeostasis and Virulence of Pseudomonas aeruginosa

Self-cleavage of the Pseudomonas aeruginosa Cell-surface Signaling Anti-sigma Factor FoxR Occurs through an N-O Acyl Rearrangement

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