Staphylococcus Aureus Fur Regulates the Expression of Virulence Factors That Contribute to the Pathogenesis of Pneumonia

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Specialty Allergy & Immunology

Date 2010 Jan 27

PMID 20100857

Citations 99

Authors

Victor J Torres

Ahmed S Attia

William J Mason

M Indriati Hood

Brian D Corbin

Federico C Beasley

Kelsi L Anderson

Devin L Stauff

W Hayes McDonald

Lisa J Zimmerman

David B Friedman

David E Heinrichs

Paul M Dunman

Eric P Skaar

Affiliations

Soon will be listed here.

Abstract

The tremendous success of Staphylococcus aureus as a pathogen is due to the controlled expression of a diverse array of virulence factors. The effects of host environments on the expression of virulence factors and the mechanisms by which S. aureus adapts to colonize distinct host tissues are largely unknown. Vertebrates have evolved to sequester nutrient iron from invading bacteria, and iron availability is a signal that alerts pathogenic microorganisms when they enter the hostile host environment. Consistent with this, we report here that S. aureus senses alterations in the iron status via the ferric uptake regulator (Fur) and alters the abundance of a large number of virulence factors. These Fur-mediated changes protect S. aureus against killing by neutrophils, and Fur is required for full staphylococcal virulence in a murine model of infection. A potential mechanistic explanation for the impact of Fur on virulence is provided by the observation that Fur coordinates the reciprocal expression of cytolysins and a subset of immunomodulatory proteins. More specifically, S. aureus lacking fur exhibits decreased expression of immunomodulatory proteins and increased expression of cytolysins. These findings reveal that Fur is involved in initiating a regulatory program that organizes the expression of virulence factors during the pathogenesis of S. aureus pneumonia.

Citing Articles

First whole genome report of PSU-3885-11 isolated from a patient in Thailand.

Chaichana N, Yaikhan T, Yingkajorn M, Thepsimanon N, Suwannasin S, Singkhamanan K Curr Res Microb Sci. 2025; 8:100350.

PMID: 39911356 PMC: 11795813. DOI: 10.1016/j.crmicr.2025.100350.

: Current perspectives on molecular pathogenesis and virulence.

Girma A Cell Surf. 2025; 13:100137.

PMID: 39758277 PMC: 11699754. DOI: 10.1016/j.tcsw.2024.100137.

The Staphylococcus aureus non-coding RNA IsrR regulates TCA cycle activity and virulence.

Rios-Delgado G, McReynolds A, Pagella E, Norambuena J, Briaud P, Zheng V Nucleic Acids Res. 2024; 53(4).

PMID: 39704109 PMC: 11879123. DOI: 10.1093/nar/gkae1243.

Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in .

Boyd J, Ryan Kaler K, Esquilin-Lebron K, Pall A, Campbell C, Foley M mBio. 2024; 15(11):e0231024.

PMID: 39440976 PMC: 11559061. DOI: 10.1128/mbio.02310-24.

Radiotracers for in situ infection imaging: Experimental considerations for in vitro microbial uptake of gallium-68-labeled siderophores.

Akter A, Cooper M, Darwesh A, Hider R, Blower P, Price N Diagn Microbiol Infect Dis. 2024; 110(4):116522.

PMID: 39340966 PMC: 11846779. DOI: 10.1016/j.diagmicrobio.2024.116522.

References

Ziebandt A, Weber H, Rudolph J, Schmid R, Hoper D, Engelmann S . Extracellular proteins of Staphylococcus aureus and the role of SarA and sigma B. Proteomics. 2001; 1(4):480-93. DOI: 10.1002/1615-9861(200104)1:4<480::AID-PROT480>3.0.CO;2-O. View

Dai J, Lee Y, Wong H . Effects of iron limitation on production of a siderophore, outer membrane proteins, and hemolysin and on hydrophobicity, cell adherence, and lethality for mice of Vibrio parahaemolyticus. Infect Immun. 1992; 60(7):2952-6. PMC: 257259. DOI: 10.1128/iai.60.7.2952-2956.1992. View

Blevins J, Beenken K, Elasri M, Hurlburt B, Smeltzer M . Strain-dependent differences in the regulatory roles of sarA and agr in Staphylococcus aureus. Infect Immun. 2002; 70(2):470-80. PMC: 127691. DOI: 10.1128/IAI.70.2.470-480.2002. View

Pichon C, Felden B . Small RNA genes expressed from Staphylococcus aureus genomic and pathogenicity islands with specific expression among pathogenic strains. Proc Natl Acad Sci U S A. 2005; 102(40):14249-54. PMC: 1242290. DOI: 10.1073/pnas.0503838102. View

Weinrick B, Dunman P, McAleese F, Murphy E, Projan S, Fang Y . Effect of mild acid on gene expression in Staphylococcus aureus. J Bacteriol. 2004; 186(24):8407-23. PMC: 532443. DOI: 10.1128/JB.186.24.8407-8423.2004. View

Masse E, Gottesman S . A small RNA regulates the expression of genes involved in iron metabolism in Escherichia coli. Proc Natl Acad Sci U S A. 2002; 99(7):4620-5. PMC: 123697. DOI: 10.1073/pnas.032066599. View

Bubeck Wardenburg J, Williams W, Missiakas D . Host defenses against Staphylococcus aureus infection require recognition of bacterial lipoproteins. Proc Natl Acad Sci U S A. 2006; 103(37):13831-6. PMC: 1564215. DOI: 10.1073/pnas.0603072103. View

Chan P, Foster S . The role of environmental factors in the regulation of virulence-determinant expression in Staphylococcus aureus 8325-4. Microbiology (Reading). 1998; 144 ( Pt 9):2469-2479. DOI: 10.1099/00221287-144-9-2469. View

Burlak C, Hammer C, Robinson M, Whitney A, McGavin M, Kreiswirth B . Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection. Cell Microbiol. 2007; 9(5):1172-90. PMC: 2064037. DOI: 10.1111/j.1462-5822.2006.00858.x. View

10.

Horsburgh M, Ingham E, Foster S . In Staphylococcus aureus, fur is an interactive regulator with PerR, contributes to virulence, and Is necessary for oxidative stress resistance through positive regulation of catalase and iron homeostasis. J Bacteriol. 2001; 183(2):468-75. PMC: 94901. DOI: 10.1128/JB.183.2.468-475.2001. View

11.

Martino M, Stabler R, Zhang Z, Farthing M, Wren B, Dorrell N . Helicobacter pylori pore-forming cytolysin orthologue TlyA possesses in vitro hemolytic activity and has a role in colonization of the gastric mucosa. Infect Immun. 2001; 69(3):1697-703. PMC: 98074. DOI: 10.1128/IAI.69.3.1697-1703.2001. View

12.

Fernandez L, Prieto M, Guijarro J . The iron- and temperature-regulated haemolysin YhlA is a virulence factor of Yersinia ruckeri. Microbiology (Reading). 2007; 153(Pt 2):483-489. DOI: 10.1099/mic.0.29284-0. View

13.

Fridkin S, Hageman J, Morrison M, Sanza L, Como-Sabetti K, Jernigan J . Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005; 352(14):1436-44. DOI: 10.1056/NEJMoa043252. View

14.

Xiong A, Singh V, Cabrera G, Jayaswal R . Molecular characterization of the ferric-uptake regulator, fur, from Staphylococcus aureus. Microbiology (Reading). 2000; 146 ( Pt 3):659-668. DOI: 10.1099/00221287-146-3-659. View

15.

Jongerius I, Kohl J, Pandey M, Ruyken M, van Kessel K, van Strijp J . Staphylococcal complement evasion by various convertase-blocking molecules. J Exp Med. 2007; 204(10):2461-71. PMC: 2118443. DOI: 10.1084/jem.20070818. View

16.

Courcol R, Trivier D, Bissinger M, Martin G, Brown M . Siderophore production by Staphylococcus aureus and identification of iron-regulated proteins. Infect Immun. 1997; 65(5):1944-8. PMC: 175248. DOI: 10.1128/iai.65.5.1944-1948.1997. View

17.

Mazmanian S, Ton-That H, Su K, Schneewind O . An iron-regulated sortase anchors a class of surface protein during Staphylococcus aureus pathogenesis. Proc Natl Acad Sci U S A. 2002; 99(4):2293-8. PMC: 122358. DOI: 10.1073/pnas.032523999. View

18.

Novick R . Genetic systems in staphylococci. Methods Enzymol. 1991; 204:587-636. DOI: 10.1016/0076-6879(91)04029-n. View

19.

Wilderman P, Sowa N, Fitzgerald D, FitzGerald P, Gottesman S, Ochsner U . Identification of tandem duplicate regulatory small RNAs in Pseudomonas aeruginosa involved in iron homeostasis. Proc Natl Acad Sci U S A. 2004; 101(26):9792-7. PMC: 470753. DOI: 10.1073/pnas.0403423101. View

20.

Gravet A, Colin D, Keller D, Girardot R, Monteil H, Prevost G . Characterization of a novel structural member, LukE-LukD, of the bi-component staphylococcal leucotoxins family. FEBS Lett. 1998; 436(2):202-8. DOI: 10.1016/s0014-5793(98)01130-2. View