title: Ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways.
abstract: ABSTRACT Chronic, biofilm-like infections by the opportunistic pathogen Pseudomonas aeruginosa are a major cause of mortality in cystic fibrosis (CF) patients. While much is known about P. aeruginosa from laboratory studies, far less is understood about what it experiences in vivo. Iron is an important environmental parameter thought to play a central role in the development and maintenance of P. aeruginosa infections, for both anabolic and signaling purposes. Previous studies have focused on ferric iron [Fe(III)] as a target for antimicrobial therapies; however, here we show that ferrous iron [Fe(II)] is abundant in the CF lung (-39 µM on average for severely sick patients) and significantly correlates with disease severity (ρ = -0.56, P = 0.004), whereas ferric iron does not (ρ = -0.28, P = 0.179). Expression of the P. aeruginosa genes bqsRS, whose transcription is upregulated in response to Fe(II), was high in the majority of patients tested, suggesting that increased Fe(II) is bioavailable to the infectious bacterial population. Because limiting Fe(III) acquisition inhibits biofilm formation by P. aeruginosa in various oxic in vitro systems, we also tested whether interfering with Fe(II) acquisition would improve biofilm control under anoxic conditions; concurrent sequestration of both iron oxidation states resulted in a 58% reduction in biofilm accumulation and 28% increase in biofilm dissolution, a significant improvement over Fe(III) chelation treatment alone. This study demonstrates that the chemistry of infected host environments coevolves with the microbial community as infections progress, which should be considered in the design of effective treatment strategies at different stages of disease.
  
  
  OBJECTIVE
  Iron is an important environmental parameter that helps pathogens thrive in sites of infection, including those of cystic fibrosis (CF) patients. Ferric iron chelation therapy has been proposed as a novel therapeutic strategy for CF lung infections, yet until now, the iron oxidation state has not been measured in the host. In studying mucus from the infected lungs of multiple CF patients from Europe and the United States, we found that ferric and ferrous iron change in concentration and relative proportion as infections progress; over time, ferrous iron comes to dominate the iron pool. This information is relevant to the design of novel CF therapeutics and, more broadly, to developing accurate models of chronic CF infections.
authors: Division of Biology, California Institute of Technology, Pasadena, California, USA.
authors: Ryan C
authors: RC
authors: Hunter
authors: Fadi
authors: F
authors: Asfour
authors: Jozef
authors: J
authors: Dingemans
authors: Brenda L
authors: BL
authors: Osuna
authors: Tahoura
authors: T
authors: Samad
authors: Anne
authors: A
authors: Malfroot
authors: Pierre
authors: P
authors: Cornelis
authors: Dianne K
authors: DK
authors: Newman
mesh_terms: D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D018441:Biofilms / Q000254:growth & development; D003550:Cystic Fibrosis / Q000473:pathology*; D005296:Ferrous Compounds / Q000032:analysis*; D020869:Gene Expression Profiling; D006801:Humans; D007501:Iron / Q000032:analysis*; D008168:Lung / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D005296:Ferrous Compounds; D007501:Iron
references: Nat Chem Biol. 2006 Mar;2(3):132-8
references: 16485005
references: PLoS Pathog. 2010 Aug 12;6(8):e1000949
references: 20711357
references: J Bacteriol. 2011 Jul;193(14):3606-17
references: 21602354
references: Biometals. 2011 Dec;24(6):1059-67
references: 21643731
references: Appl Environ Microbiol. 2006 Mar;72(3):2064-9
references: 16517655
references: J Clin Microbiol. 1997 Jun;35(6):1295-9
references: 9163432
references: J Clin Invest. 2002 Feb;109(3):317-25
references: 11827991
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Infect Immun. 2013 Aug;81(8):2697-704
references: 23690396
references: Methods Enzymol. 1994;231:502-14
references: 8041272
references: Appl Microbiol Biotechnol. 2002 Sep;59(6):718-20
references: 12226730
references: Biometals. 2009 Feb;22(1):15-22
references: 19130263
references: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8487-92
references: 16687478
references: Infect Immun. 1986 Apr;52(1):263-70
references: 2937736
references: Mol Microbiol. 2007 Jul;65(1):153-65
references: 17581126
references: Eur Respir J. 2007 Aug;30(2):286-92
references: 17504792
references: Chest. 1998 Sep;114(3):814-9
references: 9743172
references: J Cyst Fibros. 2013 Mar;12(2):154-64
references: 22951208
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16761-6
references: 18931304
references: J Clin Invest. 2007 Apr;117(4):877-88
references: 17364024
references: Thorax. 1998 Jul;53(7):594-600
references: 9797761
references: Biometals. 2004 Jun;17(3):267-70
references: 15222476
references: Biochim Biophys Acta. 2012 May;1822(5):690-713
references: 22226887
references: J Clin Microbiol. 2005 Oct;43(10):5085-90
references: 16207967
references: Chem Biol. 2005 Jul;12(7):789-96
references: 16039526
references: Environ Microbiol. 2011 Jul;13(7):1682-9
references: 21429065
references: Am J Respir Crit Care Med. 2007 Nov 15;176(10):957-69
references: 17761616
references: Am J Respir Cell Mol Biol. 2009 Sep;41(3):305-13
references: 19168700
references: Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L25-37
references: 18359885
references: Appl Environ Microbiol. 2005 Sep;71(9):5208-18
references: 16151106
references: Clin Transl Sci. 2012 Aug;5(4):368-73
references: 22883617
references: J Cyst Fibros. 2011 Mar;10(2):114-20
references: 21208831
references: J Med Microbiol. 2009 Jun;58(Pt 6):765-773
references: 19429753
references: J Cyst Fibros. 2013 Jul;12(4):390-8
references: 23176785
references: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6664-8
references: 15084751
references: J Clin Invest. 1995 Jun;95(6):2491-500
references: 7769095
references: Environ Sci Technol. 2008 Apr 1;42(7):2380-6
references: 18504969
references: Eur Respir J. 2005 Jul;26(1):153-61
references: 15994402
references: Pediatr Pulmonol. 2009 Jun;44(6):547-58
references: 19418571
references: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11076-81
references: 16043697
references: J Bacteriol. 2012 Mar;194(5):1195-204
references: 22194456
references: Nature. 2002 May 30;417(6888):552-5
references: 12037568
references: Biometals. 2006 Apr;19(2):143-57
references: 16718600
references: Am J Respir Cell Mol Biol. 2012 Dec;47(6):738-45
references: 22865623
references: Environ Sci Technol. 2007 May 1;41(9):3205-12
references: 17539527
references: Clin Microbiol Rev. 2002 Apr;15(2):167-93
references: 11932229
references: Mol Microbiol. 1999 Nov;34(3):399-413
references: 10564483
references: Nature. 2012 Jul 04;487(7405):109-13
references: 22763554
references: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):19996-20001
references: 22123963
references: Semin Respir Infect. 2002 Mar;17(1):47-56
references: 11891518
references: J Bacteriol. 2007 Nov;189(22):8079-87
references: 17873029
references: Appl Environ Microbiol. 1987 Jul;53(7):1536-40
references: 16347384