Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways

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 import...

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Autores principales:	Ryan C. Hunter, Fadi Asfour, Jozef Dingemans, Brenda L. Osuna, Tahoura Samad, Anne Malfroot, Pierre Cornelis, Dianne K. Newman
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/af2255f974e941ee96a2feb6197bdcf2
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spelling	oai:doaj.org-article:af2255f974e941ee96a2feb6197bdcf22021-11-15T15:43:09ZFerrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways10.1128/mBio.00557-132150-7511https://doaj.org/article/af2255f974e941ee96a2feb6197bdcf22013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00557-13https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Ryan C. HunterFadi AsfourJozef DingemansBrenda L. OsunaTahoura SamadAnne MalfrootPierre CornelisDianne K. NewmanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Ryan C. Hunter Fadi Asfour Jozef Dingemans Brenda L. Osuna Tahoura Samad Anne Malfroot Pierre Cornelis Dianne K. Newman Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways
description	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. IMPORTANCE 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.
format	article
author	Ryan C. Hunter Fadi Asfour Jozef Dingemans Brenda L. Osuna Tahoura Samad Anne Malfroot Pierre Cornelis Dianne K. Newman
author_facet	Ryan C. Hunter Fadi Asfour Jozef Dingemans Brenda L. Osuna Tahoura Samad Anne Malfroot Pierre Cornelis Dianne K. Newman
author_sort	Ryan C. Hunter
title	Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways
title_short	Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways
title_full	Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways
title_fullStr	Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways
title_full_unstemmed	Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways
title_sort	ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/af2255f974e941ee96a2feb6197bdcf2
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Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis Airways

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