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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2013-08-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00557-13 |
| _version_ | 1818856358959644672 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T08:23:14Z |
| format | Article |
| id | doaj.art-af2255f974e941ee96a2feb6197bdcf2 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T08:23:14Z |
| publishDate | 2013-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-af2255f974e941ee96a2feb6197bdcf22022-12-21T20:29:22ZengAmerican Society for MicrobiologymBio2150-75112013-08-014410.1128/mBio.00557-13Ferrous Iron Is a Significant Component of Bioavailable Iron in Cystic Fibrosis AirwaysRyan C. Hunter0Fadi Asfour1Jozef Dingemans2Brenda L. Osuna3Tahoura Samad4Anne Malfroot5Pierre Cornelis6Dianne K. Newman7Division of Biology, California Institute of Technology, Pasadena, California, USADepartment of Pediatric Pulmonology, Children’s Hospital of Los Angeles, Los Angeles, California, USADepartment of Bioengineering Sciences, Research Group Microbiology, Flanders Interuniversity Institute of Biotechnology (VIB), Vrije Universiteit Brussel, Brussels, BelgiumStatistical Consulting, Information Technology Services, University of Southern California, Los Angeles, California, USADivision of Biology, California Institute of Technology, Pasadena, California, USACystic Fibrosis Clinic, Universitair Ziekenhuis Brussel (UZB), Brussels, BelgiumDepartment of Bioengineering Sciences, Research Group Microbiology, Flanders Interuniversity Institute of Biotechnology (VIB), Vrije Universiteit Brussel, Brussels, BelgiumDivision of Biology, California Institute of Technology, Pasadena, California, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.00557-13 |
| spellingShingle | 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 mBio |
| title | 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_short | 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 |
| url | https://journals.asm.org/doi/10.1128/mBio.00557-13 |
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