Pseudomonas aeruginosa cytotoxicity is attenuated at high cell density and associated with the accumulation of phenylacetic acid
P. aeruginosa is known to cause acute cytotoxicity against various human and animal cells and tissues. Intriguingly, however, in this study we noticed that while a low cell density inoculum of P. aeruginosa caused severe cytotoxicity against human lung tissue cell line A549, increasing the cell dens...
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| creator | Wang, Jianhe Dong, Yihu Zhou, Tielin Liu, Xiaoling Deng, Yinyue Wang, Chao Lee, Jasmine Zhang, Lian-Hui |
| description | P. aeruginosa is known to cause acute cytotoxicity against various human and animal cells and tissues.
Intriguingly, however, in this study we noticed that while a low cell density inoculum of P. aeruginosa caused severe cytotoxicity against human lung tissue cell line A549, increasing the cell density of bacterial inoculum led to decreased cytotoxicity. Addition of the supernatants from high density bacterial culture to low cell density inoculum protected the human cells from bacterial cytotoxic damage, suggesting that P. aeruginosa may produce and accumulate an inhibitory molecule(s) counteracting its pathogenic infection. The inhibitor was purified from the stationary-phase culture supernatants of P. aeruginosa strain PAO1 using bioassay-guided high performance liquid chromatography (HPLC), and characterized to be phenylacetic acid (PAA) by mass spectrometry and nuclear magnetic resonance spectroscopy. Microarray analysis revealed that treatment of P. aeruginosa with PAA down-regulated the transcriptional expression of Type III secretion system (T3SS) genes and related regulatory genes including rsmA and vfr, which were confirmed by transcriptional and translational analysis.
Identification of bacterial metabolite PAA as a T3SS-specific inhibitor explains this intriguing inverse cell-density-dependent-cytotoxicity phenomenon as T3SS is known to be a key virulence factor associated with cytotoxicity and acute infection. The findings may provide useful clues for design and development of new strategies to combat this formidable bacterial pathogen. |
| doi_str_mv | 10.1371/journal.pone.0060187 |
| format | Article |
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Intriguingly, however, in this study we noticed that while a low cell density inoculum of P. aeruginosa caused severe cytotoxicity against human lung tissue cell line A549, increasing the cell density of bacterial inoculum led to decreased cytotoxicity. Addition of the supernatants from high density bacterial culture to low cell density inoculum protected the human cells from bacterial cytotoxic damage, suggesting that P. aeruginosa may produce and accumulate an inhibitory molecule(s) counteracting its pathogenic infection. The inhibitor was purified from the stationary-phase culture supernatants of P. aeruginosa strain PAO1 using bioassay-guided high performance liquid chromatography (HPLC), and characterized to be phenylacetic acid (PAA) by mass spectrometry and nuclear magnetic resonance spectroscopy. Microarray analysis revealed that treatment of P. aeruginosa with PAA down-regulated the transcriptional expression of Type III secretion system (T3SS) genes and related regulatory genes including rsmA and vfr, which were confirmed by transcriptional and translational analysis.
Identification of bacterial metabolite PAA as a T3SS-specific inhibitor explains this intriguing inverse cell-density-dependent-cytotoxicity phenomenon as T3SS is known to be a key virulence factor associated with cytotoxicity and acute infection. The findings may provide useful clues for design and development of new strategies to combat this formidable bacterial pathogen.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0060187</identifier><identifier>PMID: 23555919</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Bacteria ; Bacterial Proteins - metabolism ; Bioassays ; Biology ; Cell culture ; Cell density ; Cell Line ; Chromatography ; Chromatography, High Pressure Liquid ; Cytotoxicity ; Damage accumulation ; Density ; DNA microarrays ; Gene expression ; Genes ; High performance liquid chromatography ; Humans ; Infections ; Inhibitors ; Inoculum ; Kinases ; Laboratories ; Liquid chromatography ; Lungs ; Magnetic resonance ; Magnetic resonance spectroscopy ; Mass spectrometry ; Mass spectroscopy ; Metabolism ; Mutation ; NMR ; Nuclear magnetic resonance ; Pathogens ; Phenylacetates - metabolism ; Phenylacetic acid ; Proteins ; Pseudomonas aeruginosa ; Pseudomonas aeruginosa - cytology ; Pseudomonas aeruginosa - metabolism ; Pseudomonas aeruginosa - pathogenicity ; Secretion ; Spectroscopy ; Tissues ; Toxicity ; Transcription ; Virulence ; Virulence - physiology ; Virulence factors</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e60187</ispartof><rights>2013 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Wang et al 2013 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-39f68845c4ca335fa72eadc818ccadf9e4cbcf345dd7ca6b886b7848fe2f9fe3</citedby><cites>FETCH-LOGICAL-c526t-39f68845c4ca335fa72eadc818ccadf9e4cbcf345dd7ca6b886b7848fe2f9fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612096/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612096/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2930,23873,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23555919$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>II, Roy Martin Roop</contributor><creatorcontrib>Wang, Jianhe</creatorcontrib><creatorcontrib>Dong, Yihu</creatorcontrib><creatorcontrib>Zhou, Tielin</creatorcontrib><creatorcontrib>Liu, Xiaoling</creatorcontrib><creatorcontrib>Deng, Yinyue</creatorcontrib><creatorcontrib>Wang, Chao</creatorcontrib><creatorcontrib>Lee, Jasmine</creatorcontrib><creatorcontrib>Zhang, Lian-Hui</creatorcontrib><title>Pseudomonas aeruginosa cytotoxicity is attenuated at high cell density and associated with the accumulation of phenylacetic acid</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>P. aeruginosa is known to cause acute cytotoxicity against various human and animal cells and tissues.
Intriguingly, however, in this study we noticed that while a low cell density inoculum of P. aeruginosa caused severe cytotoxicity against human lung tissue cell line A549, increasing the cell density of bacterial inoculum led to decreased cytotoxicity. Addition of the supernatants from high density bacterial culture to low cell density inoculum protected the human cells from bacterial cytotoxic damage, suggesting that P. aeruginosa may produce and accumulate an inhibitory molecule(s) counteracting its pathogenic infection. The inhibitor was purified from the stationary-phase culture supernatants of P. aeruginosa strain PAO1 using bioassay-guided high performance liquid chromatography (HPLC), and characterized to be phenylacetic acid (PAA) by mass spectrometry and nuclear magnetic resonance spectroscopy. Microarray analysis revealed that treatment of P. aeruginosa with PAA down-regulated the transcriptional expression of Type III secretion system (T3SS) genes and related regulatory genes including rsmA and vfr, which were confirmed by transcriptional and translational analysis.
Identification of bacterial metabolite PAA as a T3SS-specific inhibitor explains this intriguing inverse cell-density-dependent-cytotoxicity phenomenon as T3SS is known to be a key virulence factor associated with cytotoxicity and acute infection. The findings may provide useful clues for design and development of new strategies to combat this formidable bacterial pathogen.</description><subject>Acids</subject><subject>Bacteria</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bioassays</subject><subject>Biology</subject><subject>Cell culture</subject><subject>Cell density</subject><subject>Cell Line</subject><subject>Chromatography</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cytotoxicity</subject><subject>Damage accumulation</subject><subject>Density</subject><subject>DNA microarrays</subject><subject>Gene expression</subject><subject>Genes</subject><subject>High performance liquid chromatography</subject><subject>Humans</subject><subject>Infections</subject><subject>Inhibitors</subject><subject>Inoculum</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Liquid chromatography</subject><subject>Lungs</subject><subject>Magnetic resonance</subject><subject>Magnetic resonance spectroscopy</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Metabolism</subject><subject>Mutation</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Pathogens</subject><subject>Phenylacetates - metabolism</subject><subject>Phenylacetic acid</subject><subject>Proteins</subject><subject>Pseudomonas aeruginosa</subject><subject>Pseudomonas aeruginosa - cytology</subject><subject>Pseudomonas aeruginosa - metabolism</subject><subject>Pseudomonas aeruginosa - pathogenicity</subject><subject>Secretion</subject><subject>Spectroscopy</subject><subject>Tissues</subject><subject>Toxicity</subject><subject>Transcription</subject><subject>Virulence</subject><subject>Virulence - physiology</subject><subject>Virulence factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uk1v1DAQjRCIlsI_QBCJ8y527DjOBQlVfFSqBIfercl4vPEqay-xQ9kbP51sN63aAyeP_D7mafSK4i1nay4a_nEbpzHAsN7HQGvGFOO6eVac81ZUK1Ux8fzRfFa8SmnLWC20Ui-Ls0rUdd3y9rz4-zPRZOMuBkgl0DhtfIgJSjzkmOMfjz4fSj9DOVOYIJOdx7L3m75EGobSUkhHCoQZSCmiv-Pc-tyXuacSEKfdNED2MZTRlfuewmEApOxxBr19XbxwMCR6s7wXxc3XLzeX31fXP75dXX6-XmFdqbwSrVNayxolghC1g6YisKi5RgTrWpLYoROytrZBUJ3Wqmu01I4q1zoSF8X7k-1-iMkst0uGC8FapmtdzYyrE8NG2Jr96HcwHkwEb-4-4rgxMM6pBzJEjXOSS2mbSlrEDlA7KRRV4MCqdvb6tGybuh1ZpJBHGJ6YPkWC780m_jZC8Yq1ajb4sBiM8ddEKf8nsjyxcIwpjeQeNnBmjiW5V5ljScxSkln27nG6B9F9K8Q_TavA4g</recordid><startdate>20130329</startdate><enddate>20130329</enddate><creator>Wang, Jianhe</creator><creator>Dong, Yihu</creator><creator>Zhou, Tielin</creator><creator>Liu, Xiaoling</creator><creator>Deng, Yinyue</creator><creator>Wang, Chao</creator><creator>Lee, Jasmine</creator><creator>Zhang, Lian-Hui</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130329</creationdate><title>Pseudomonas aeruginosa cytotoxicity is attenuated at high cell density and associated with the accumulation of phenylacetic acid</title><author>Wang, Jianhe ; Dong, Yihu ; Zhou, Tielin ; Liu, Xiaoling ; Deng, Yinyue ; Wang, Chao ; Lee, Jasmine ; Zhang, Lian-Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-39f68845c4ca335fa72eadc818ccadf9e4cbcf345dd7ca6b886b7848fe2f9fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acids</topic><topic>Bacteria</topic><topic>Bacterial Proteins - 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Intriguingly, however, in this study we noticed that while a low cell density inoculum of P. aeruginosa caused severe cytotoxicity against human lung tissue cell line A549, increasing the cell density of bacterial inoculum led to decreased cytotoxicity. Addition of the supernatants from high density bacterial culture to low cell density inoculum protected the human cells from bacterial cytotoxic damage, suggesting that P. aeruginosa may produce and accumulate an inhibitory molecule(s) counteracting its pathogenic infection. The inhibitor was purified from the stationary-phase culture supernatants of P. aeruginosa strain PAO1 using bioassay-guided high performance liquid chromatography (HPLC), and characterized to be phenylacetic acid (PAA) by mass spectrometry and nuclear magnetic resonance spectroscopy. Microarray analysis revealed that treatment of P. aeruginosa with PAA down-regulated the transcriptional expression of Type III secretion system (T3SS) genes and related regulatory genes including rsmA and vfr, which were confirmed by transcriptional and translational analysis.
Identification of bacterial metabolite PAA as a T3SS-specific inhibitor explains this intriguing inverse cell-density-dependent-cytotoxicity phenomenon as T3SS is known to be a key virulence factor associated with cytotoxicity and acute infection. The findings may provide useful clues for design and development of new strategies to combat this formidable bacterial pathogen.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23555919</pmid><doi>10.1371/journal.pone.0060187</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acids Bacteria Bacterial Proteins - metabolism Bioassays Biology Cell culture Cell density Cell Line Chromatography Chromatography, High Pressure Liquid Cytotoxicity Damage accumulation Density DNA microarrays Gene expression Genes High performance liquid chromatography Humans Infections Inhibitors Inoculum Kinases Laboratories Liquid chromatography Lungs Magnetic resonance Magnetic resonance spectroscopy Mass spectrometry Mass spectroscopy Metabolism Mutation NMR Nuclear magnetic resonance Pathogens Phenylacetates - metabolism Phenylacetic acid Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa - cytology Pseudomonas aeruginosa - metabolism Pseudomonas aeruginosa - pathogenicity Secretion Spectroscopy Tissues Toxicity Transcription Virulence Virulence - physiology Virulence factors |
| title | Pseudomonas aeruginosa cytotoxicity is attenuated at high cell density and associated with the accumulation of phenylacetic acid |
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