Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence
The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation s...
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| Veröffentlicht in: | The Journal of experimental medicine 2004-11, Vol.200 (9), p.1213-1219 |
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| creator | Schrettl, Markus Bignell, Elaine Kragl, Claudia Joechl, Chistoph Rogers, Tom Arst, Jr, Herbert N Haynes, Ken Haas, Hubertus |
| description | The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus L-ornithine-N5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog-and the fungal siderophore system in general-in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies. |
| doi_str_mv | 10.1084/jem.20041242 |
| format | Article |
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Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus L-ornithine-N5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog-and the fungal siderophore system in general-in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>EISSN: 1892-1007</identifier><identifier>DOI: 10.1084/jem.20041242</identifier><identifier>PMID: 15504822</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; Aspergillus fumigatus ; Aspergillus fumigatus - enzymology ; Aspergillus fumigatus - metabolism ; Aspergillus fumigatus - pathogenicity ; Base Sequence ; Blotting, Northern ; Brief Definitive Report ; Chromatography, High Pressure Liquid ; DNA Primers ; DNA, Complementary - genetics ; Fungal Proteins - genetics ; Iron - metabolism ; Mice ; Mixed Function Oxygenases - genetics ; Mixed Function Oxygenases - metabolism ; Molecular Sequence Data ; Mutation - genetics ; Phenotype ; Plasmids - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Siderophores - biosynthesis</subject><ispartof>The Journal of experimental medicine, 2004-11, Vol.200 (9), p.1213-1219</ispartof><rights>Copyright © 2004, The Rockefeller University Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3262-ffaf7aee1758870a226ea6c0bdd9746325205c73e8d2c8230778314ec7e66c153</citedby><cites>FETCH-LOGICAL-c3262-ffaf7aee1758870a226ea6c0bdd9746325205c73e8d2c8230778314ec7e66c153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15504822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schrettl, Markus</creatorcontrib><creatorcontrib>Bignell, Elaine</creatorcontrib><creatorcontrib>Kragl, Claudia</creatorcontrib><creatorcontrib>Joechl, Chistoph</creatorcontrib><creatorcontrib>Rogers, Tom</creatorcontrib><creatorcontrib>Arst, Jr, Herbert N</creatorcontrib><creatorcontrib>Haynes, Ken</creatorcontrib><creatorcontrib>Haas, Hubertus</creatorcontrib><title>Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus L-ornithine-N5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog-and the fungal siderophore system in general-in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies.</description><subject>Animals</subject><subject>Aspergillus fumigatus</subject><subject>Aspergillus fumigatus - enzymology</subject><subject>Aspergillus fumigatus - metabolism</subject><subject>Aspergillus fumigatus - pathogenicity</subject><subject>Base Sequence</subject><subject>Blotting, Northern</subject><subject>Brief Definitive Report</subject><subject>Chromatography, High Pressure Liquid</subject><subject>DNA Primers</subject><subject>DNA, Complementary - genetics</subject><subject>Fungal Proteins - genetics</subject><subject>Iron - metabolism</subject><subject>Mice</subject><subject>Mixed Function Oxygenases - genetics</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Molecular Sequence Data</subject><subject>Mutation - genetics</subject><subject>Phenotype</subject><subject>Plasmids - genetics</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Sequence Analysis, DNA</subject><subject>Siderophores - biosynthesis</subject><issn>0022-1007</issn><issn>1540-9538</issn><issn>1892-1007</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1rHDEQxUVIiM9OutRBVaqsM_rWNQFjnDhgSGGnFjrt7J2MdnWRdg_831vBl6_K1cwwP9684RHyjsE5Ays_3eN4zgEk45K_ICumJHRrJexLsgLgvGMA5oSc1noPwKRU-jU5YUqBtJyvyHgbeyx5v8sF6Sbm-jDNO6yx0s0y0ynPtGC_hDkekMaSJ-prjWNMfo5taBjWitMcfaJDLvSi7rFsY0pLpcMyxq2fW3eIZUk4BXxDXg0-VXx7rGfkx5eru8vr7ub712-XFzddEFzzbhj8YDwiM8paA55zjV4H2PT92kgtuOKgghFoex4sF2CMFUxiMKh1YEqckc9PuvtlM2IfmsPik9uXOPry4LKP7v_NFHdumw-Oc8as1k3gw1Gg5J8L1tmNsQZMyU-Yl-q0ASFYO_0cyIxhYi3XDfz4BIaSay04_HHDwP0K0rUg3e8gG_7-3w_-wsfkxCNDtpyi</recordid><startdate>20041101</startdate><enddate>20041101</enddate><creator>Schrettl, Markus</creator><creator>Bignell, Elaine</creator><creator>Kragl, Claudia</creator><creator>Joechl, Chistoph</creator><creator>Rogers, Tom</creator><creator>Arst, Jr, Herbert N</creator><creator>Haynes, Ken</creator><creator>Haas, Hubertus</creator><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>M7N</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20041101</creationdate><title>Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence</title><author>Schrettl, Markus ; Bignell, Elaine ; Kragl, Claudia ; Joechl, Chistoph ; Rogers, Tom ; Arst, Jr, Herbert N ; Haynes, Ken ; Haas, Hubertus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3262-ffaf7aee1758870a226ea6c0bdd9746325205c73e8d2c8230778314ec7e66c153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Aspergillus fumigatus</topic><topic>Aspergillus fumigatus - enzymology</topic><topic>Aspergillus fumigatus - metabolism</topic><topic>Aspergillus fumigatus - pathogenicity</topic><topic>Base Sequence</topic><topic>Blotting, Northern</topic><topic>Brief Definitive Report</topic><topic>Chromatography, High Pressure Liquid</topic><topic>DNA Primers</topic><topic>DNA, Complementary - genetics</topic><topic>Fungal Proteins - genetics</topic><topic>Iron - metabolism</topic><topic>Mice</topic><topic>Mixed Function Oxygenases - genetics</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Molecular Sequence Data</topic><topic>Mutation - genetics</topic><topic>Phenotype</topic><topic>Plasmids - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Sequence Analysis, DNA</topic><topic>Siderophores - biosynthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schrettl, Markus</creatorcontrib><creatorcontrib>Bignell, Elaine</creatorcontrib><creatorcontrib>Kragl, Claudia</creatorcontrib><creatorcontrib>Joechl, Chistoph</creatorcontrib><creatorcontrib>Rogers, Tom</creatorcontrib><creatorcontrib>Arst, Jr, Herbert N</creatorcontrib><creatorcontrib>Haynes, Ken</creatorcontrib><creatorcontrib>Haas, Hubertus</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schrettl, Markus</au><au>Bignell, Elaine</au><au>Kragl, Claudia</au><au>Joechl, Chistoph</au><au>Rogers, Tom</au><au>Arst, Jr, Herbert N</au><au>Haynes, Ken</au><au>Haas, Hubertus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2004-11-01</date><risdate>2004</risdate><volume>200</volume><issue>9</issue><spage>1213</spage><epage>1219</epage><pages>1213-1219</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><eissn>1892-1007</eissn><abstract>The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus L-ornithine-N5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. 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| subjects | Animals Aspergillus fumigatus Aspergillus fumigatus - enzymology Aspergillus fumigatus - metabolism Aspergillus fumigatus - pathogenicity Base Sequence Blotting, Northern Brief Definitive Report Chromatography, High Pressure Liquid DNA Primers DNA, Complementary - genetics Fungal Proteins - genetics Iron - metabolism Mice Mixed Function Oxygenases - genetics Mixed Function Oxygenases - metabolism Molecular Sequence Data Mutation - genetics Phenotype Plasmids - genetics Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA Siderophores - biosynthesis |
| title | Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence |
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