Replication of Crohn’s Disease Mucosal E. coli Isolates inside Macrophages Correlates with Resistance to Superoxide and Is Dependent on Macrophage NF-kappa B Activation
Identifieur interne : 000427 ( Pmc/Checkpoint ); précédent : 000426; suivant : 000428Replication of Crohn’s Disease Mucosal E. coli Isolates inside Macrophages Correlates with Resistance to Superoxide and Is Dependent on Macrophage NF-kappa B Activation
Auteurs : Ahmed Tawfik [Irlande (pays)] ; Paul Knight [Royaume-Uni] ; Carrie A. Duckworth ; D. Mark Pritchard ; Jonathan M. Rhodes ; Barry J. CampbellSource :
- Pathogens [ 2076-0817 ] ; 2019.
Abstract
Mucosa-associated
Url:
DOI: 10.3390/pathogens8020074
PubMed: 31181736
PubMed Central: 6630736
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Replication of Crohn’s Disease Mucosal <italic>E. coli</italic> Isolates inside Macrophages Correlates with Resistance to Superoxide and Is Dependent on Macrophage NF-kappa B Activation</title><author><name sortKey="Tawfik, Ahmed" sort="Tawfik, Ahmed" uniqKey="Tawfik A" first="Ahmed" last="Tawfik">Ahmed Tawfik</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-pathogens-08-00074">Gastroenterology Department, Beaumont Hospital, Dublin 9, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>Gastroenterology Department, Beaumont Hospital, Dublin 9</wicri:regionArea><wicri:noRegion>Dublin 9</wicri:noRegion></affiliation></author><author><name sortKey="Knight, Paul" sort="Knight, Paul" uniqKey="Knight P" first="Paul" last="Knight">Paul Knight</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-pathogens-08-00074">Gastroenterology Department, University Hospital of South Manchester, Wythenshawe M23 9LT, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Gastroenterology Department, University Hospital of South Manchester, Wythenshawe M23 9LT</wicri:regionArea><wicri:noRegion>Wythenshawe M23 9LT</wicri:noRegion></affiliation></author><author><name sortKey="Duckworth, Carrie A" sort="Duckworth, Carrie A" uniqKey="Duckworth C" first="Carrie A." last="Duckworth">Carrie A. Duckworth</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author><author><name sortKey="Pritchard, D Mark" sort="Pritchard, D Mark" uniqKey="Pritchard D" first="D. Mark" last="Pritchard">D. Mark Pritchard</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author><author><name sortKey="Rhodes, Jonathan M" sort="Rhodes, Jonathan M" uniqKey="Rhodes J" first="Jonathan M." last="Rhodes">Jonathan M. Rhodes</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author><author><name sortKey="Campbell, Barry J" sort="Campbell, Barry J" uniqKey="Campbell B" first="Barry J." last="Campbell">Barry J. Campbell</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31181736</idno><idno type="pmc">6630736</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630736</idno><idno type="RBID">PMC:6630736</idno><idno type="doi">10.3390/pathogens8020074</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000789</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000789</idno><idno type="wicri:Area/Pmc/Curation">000789</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000789</idno><idno type="wicri:Area/Pmc/Checkpoint">000427</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000427</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Replication of Crohn’s Disease Mucosal <italic>E. coli</italic> Isolates inside Macrophages Correlates with Resistance to Superoxide and Is Dependent on Macrophage NF-kappa B Activation</title><author><name sortKey="Tawfik, Ahmed" sort="Tawfik, Ahmed" uniqKey="Tawfik A" first="Ahmed" last="Tawfik">Ahmed Tawfik</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-pathogens-08-00074">Gastroenterology Department, Beaumont Hospital, Dublin 9, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>Gastroenterology Department, Beaumont Hospital, Dublin 9</wicri:regionArea><wicri:noRegion>Dublin 9</wicri:noRegion></affiliation></author><author><name sortKey="Knight, Paul" sort="Knight, Paul" uniqKey="Knight P" first="Paul" last="Knight">Paul Knight</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-pathogens-08-00074">Gastroenterology Department, University Hospital of South Manchester, Wythenshawe M23 9LT, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Gastroenterology Department, University Hospital of South Manchester, Wythenshawe M23 9LT</wicri:regionArea><wicri:noRegion>Wythenshawe M23 9LT</wicri:noRegion></affiliation></author><author><name sortKey="Duckworth, Carrie A" sort="Duckworth, Carrie A" uniqKey="Duckworth C" first="Carrie A." last="Duckworth">Carrie A. Duckworth</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author><author><name sortKey="Pritchard, D Mark" sort="Pritchard, D Mark" uniqKey="Pritchard D" first="D. Mark" last="Pritchard">D. Mark Pritchard</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author><author><name sortKey="Rhodes, Jonathan M" sort="Rhodes, Jonathan M" uniqKey="Rhodes J" first="Jonathan M." last="Rhodes">Jonathan M. Rhodes</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author><author><name sortKey="Campbell, Barry J" sort="Campbell, Barry J" uniqKey="Campbell B" first="Barry J." last="Campbell">Barry J. Campbell</name><affiliation><nlm:aff id="af1-pathogens-08-00074">Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</nlm:aff></affiliation></author></analytic><series><title level="j">Pathogens</title><idno type="eISSN">2076-0817</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Mucosa-associated <italic>Escherichia coli</italic> are increased in Crohn’s disease (CD) and colorectal cancer (CRC). CD isolates replicate within macrophages but the specificity of this effect for CD and its mechanism are unclear. Gentamicin exclusion assay was used to assess <italic>E. coli</italic> replication within J774.A1 murine macrophages. <italic>E. coli</italic> growth was assessed following acid, low-nutrient, nitrosative, oxidative and superoxide stress, mimicking the phagolysosome. Twelve of 16 CD <italic>E. coli</italic> isolates replicated >2-fold within J774.A1 macrophages; likewise for isolates from 6/7 urinary tract infection (UTI), 8/9 from healthy subjects, compared with 2/6 ulcerative colitis, 2/7 colorectal cancer and 0/3 laboratory strains. CD mucosal <italic>E. coli</italic> were tolerant of acidic, low-nutrient, nitrosative and oxidative stress. Replication within macrophages correlated strongly with tolerance to superoxide stress (rho = 0.44, <italic>p</italic> = 0.0009). Exemplar CD <italic>E. coli</italic> HM605 and LF82 were unable to survive within <italic>Nfκb1<sup>-/-</sup></italic> murine bone marrow-derived macrophages. In keeping with this, pre-incubation of macrophages with hydrocortisone (0.6 µM for 24 h) caused 70.49 ± 12.11% inhibition of intra-macrophage replication. Thus, CD mucosal <italic>E. coli</italic> commonly replicate inside macrophages, but so do some UTI and healthy subject strains. Replication correlates with resistance to superoxide and is highly dependent on macrophage NF-κB signalling. This may therefore be a good therapeutic target.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Darfeuille Michaud, A" uniqKey="Darfeuille Michaud A">A. Darfeuille-Michaud</name></author><author><name sortKey="Neut, C" uniqKey="Neut C">C. Neut</name></author><author><name sortKey="Barnich, N" uniqKey="Barnich N">N. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pathogens</journal-id><journal-id journal-id-type="iso-abbrev">Pathogens</journal-id><journal-id journal-id-type="publisher-id">pathogens</journal-id><journal-title-group><journal-title>Pathogens</journal-title></journal-title-group><issn pub-type="epub">2076-0817</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31181736</article-id><article-id pub-id-type="pmc">6630736</article-id><article-id pub-id-type="doi">10.3390/pathogens8020074</article-id><article-id pub-id-type="publisher-id">pathogens-08-00074</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Replication of Crohn’s Disease Mucosal <italic>E. coli</italic> Isolates inside Macrophages Correlates with Resistance to Superoxide and Is Dependent on Macrophage NF-kappa B Activation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tawfik</surname><given-names>Ahmed</given-names></name><xref ref-type="aff" rid="af1-pathogens-08-00074">1</xref><xref ref-type="aff" rid="af2-pathogens-08-00074">2</xref></contrib><contrib contrib-type="author"><name><surname>Knight</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="af1-pathogens-08-00074">1</xref><xref ref-type="aff" rid="af3-pathogens-08-00074">3</xref></contrib><contrib contrib-type="author"><name><surname>Duckworth</surname><given-names>Carrie A.</given-names></name><xref ref-type="aff" rid="af1-pathogens-08-00074">1</xref></contrib><contrib contrib-type="author"><name><surname>Pritchard</surname><given-names>D. Mark</given-names></name><xref ref-type="aff" rid="af1-pathogens-08-00074">1</xref></contrib><contrib contrib-type="author"><name><surname>Rhodes</surname><given-names>Jonathan M.</given-names></name><xref ref-type="aff" rid="af1-pathogens-08-00074">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7407-012X</contrib-id><name><surname>Campbell</surname><given-names>Barry J.</given-names></name><xref ref-type="aff" rid="af1-pathogens-08-00074">1</xref><xref rid="c1-pathogens-08-00074" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-pathogens-08-00074"><label>1</label>Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK;<email>ahmedtawfik13@yahoo.com</email> (A.T.);<email>paul.knight@mft.nhs.uk</email> (P.K.);<email>carried@liv.ac.uk</email> (C.A.D.);<email>dmpritch@liv.ac.uk</email> (D.M.P.);<email>rhodesjm@liv.ac.uk</email> (J.M.R.)</aff><aff id="af2-pathogens-08-00074"><label>2</label>Gastroenterology Department, Beaumont Hospital, Dublin 9, Ireland</aff><aff id="af3-pathogens-08-00074"><label>3</label>Gastroenterology Department, University Hospital of South Manchester, Wythenshawe M23 9LT, UK</aff><author-notes><corresp id="c1-pathogens-08-00074"><label>*</label>Correspondence: <email>bjcampbl@liv.ac.uk</email>; Tel.: +44-151-794-6829</corresp></author-notes><pub-date pub-type="epub"><day>08</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>6</month><year>2019</year></pub-date><volume>8</volume><issue>2</issue><elocation-id>74</elocation-id><history><date date-type="received"><day>29</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>06</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Mucosa-associated <italic>Escherichia coli</italic> are increased in Crohn’s disease (CD) and colorectal cancer (CRC). CD isolates replicate within macrophages but the specificity of this effect for CD and its mechanism are unclear. Gentamicin exclusion assay was used to assess <italic>E. coli</italic> replication within J774.A1 murine macrophages. <italic>E. coli</italic> growth was assessed following acid, low-nutrient, nitrosative, oxidative and superoxide stress, mimicking the phagolysosome. Twelve of 16 CD <italic>E. coli</italic> isolates replicated >2-fold within J774.A1 macrophages; likewise for isolates from 6/7 urinary tract infection (UTI), 8/9 from healthy subjects, compared with 2/6 ulcerative colitis, 2/7 colorectal cancer and 0/3 laboratory strains. CD mucosal <italic>E. coli</italic> were tolerant of acidic, low-nutrient, nitrosative and oxidative stress. Replication within macrophages correlated strongly with tolerance to superoxide stress (rho = 0.44, <italic>p</italic> = 0.0009). Exemplar CD <italic>E. coli</italic> HM605 and LF82 were unable to survive within <italic>Nfκb1<sup>-/-</sup></italic> murine bone marrow-derived macrophages. In keeping with this, pre-incubation of macrophages with hydrocortisone (0.6 µM for 24 h) caused 70.49 ± 12.11% inhibition of intra-macrophage replication. Thus, CD mucosal <italic>E. coli</italic> commonly replicate inside macrophages, but so do some UTI and healthy subject strains. Replication correlates with resistance to superoxide and is highly dependent on macrophage NF-κB signalling. This may therefore be a good therapeutic target.</p></abstract><kwd-group><kwd><italic>Escherichia coli</italic></kwd><kwd>Crohn’s disease</kwd><kwd>macrophage</kwd><kwd>phagolysosome</kwd><kwd>superoxide</kwd><kwd>hydrocortisone</kwd><kwd>Nuclear factor kappa B</kwd></kwd-group></article-meta></front><floats-group><fig id="pathogens-08-00074-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Crohn’s disease mucosa-associated <italic>E. coli</italic> isolates show significant intra-macrophage replication. Replication of 48 <italic>E. coli</italic> (<italic>n</italic> = 16 CD, <italic>n</italic> = 7 CRC, <italic>n</italic> = 6 UC, <italic>n</italic> = 9 HC, <italic>n</italic> = 7 UTI and <italic>n</italic> = 3 laboratory strains) was assessed by overnight bacterial culture of J774.A1 murine macrophage cell lysates following a gentamicin protection assay. Data are expressed as fold change [mean ± SD] of recovered intra-macrophage bacteria 6 h post-infection compared to the number of viable colony-forming units (cfu) obtained immediately after a 1-h gentamicin treatment step (i.e., 3 h post-infection). <italic>N</italic> = 3 independent experiments, <italic>n</italic> = 3 replicates, excepting for <italic>E. coli</italic> LF82 and EPI300 (<italic>N</italic> = 9, <italic>n</italic> = 3), and HM605 (<italic>N</italic> = 6, <italic>n</italic> = 3). Significant differences are indicated as follows: *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01 and ***<italic>p</italic> < 0.001; ANOVA with Dunnett’s post hoc test compared to control (non-replicating laboratory <italic>E. coli</italic> EPI300).</p></caption><graphic xlink:href="pathogens-08-00074-g001"></graphic></fig><fig id="pathogens-08-00074-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Mucosa-associated <italic>E. coli</italic> strains all tolerate acidic, nitrosative and oxidative stress but vary considerably in their ability to tolerate superoxide stress that mimics the phagolysosome environment. CD mucosa-associated <italic>E. coli</italic> strains LF82 (<bold>A</bold>), HM427 (<bold>B</bold>), HM605 (<bold>C</bold>) and HM615 (<bold>D</bold>) (black bars) showed significant ability to tolerate acidic stress (LB agar containing 100 mM morpholine ethanesulphonic acid [MES], pH 5.0), nitrosative stress (LB agar containing 100 mM MES pH 5.0 and 1mM NaNO<sub>2</sub>), oxidative stress (LB agar containing 1 mM H<sub>2</sub>O<sub>2</sub>, pH 7.0) and superoxide stress (LB agar containing 1 mM methyl viologen, pH 7.0), compared to growth on reference LB agar pH 7.0. <italic>E. coli</italic> K-12 (E), was also tolerant to all stress conditions. Conversely, laboratory <italic>E. coli</italic> strains EPI300 (<bold>F</bold>) and XL-1Blue (<bold>G</bold>) (grey bars) were intolerant to all studied stress conditions, especially superoxide stress (ng = no growth), and colorectal cancer (CRC) <italic>E. coli</italic> strain HM358 (H) (white bars) was intolerant only to superoxide stress. Significant differences from growth on LB agar pH 7.0; *<italic>p</italic> < 0.05, **<italic>p</italic> < 0.01, ***<italic>p</italic> < 0.001, ANOVA with Dunnett’s post hoc test (<italic>N</italic> = 4 experiments, <italic>n</italic> = 3 replicates).</p></caption><graphic xlink:href="pathogens-08-00074-g002"></graphic></fig><fig id="pathogens-08-00074-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Stress tolerance heatmap of <italic>E. coli</italic> growth on solid media under conditions that mimic the phagolysosome environment. Data expressed as mean % bacterial growth under stress conditions (blue = intolerant, red = high tolerance) compared to growth on reference LB agar pH 7.0 (100%); <italic>N</italic> = 4 experiments, <italic>n</italic> = 3 replicates. Acidic stress (LB agar containing 100 mM morpholine ethanesulphonic acid [MES] pH 5.0); oxidative stress (LB agar containing 1 mM H<sub>2</sub>O<sub>2</sub> pH 7.0); and superoxide stress (LB agar containing 1 mM methyl viologen pH 7.0). CD, Crohn’s disease; CRC, colorectal cancer; UC, ulcerative colitis; UTI, urinary tract infection; HC, healthy controls; LAB, Laboratory strains.</p></caption><graphic xlink:href="pathogens-08-00074-g003"></graphic></fig><fig id="pathogens-08-00074-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Correlation between growth of <italic>E. coli</italic> strains under superoxide stress conditions and their ability to replicate within macrophages. Spearman’s rank correlation shows a monotonic direct relationship between growth of 48 <italic>E. coli</italic>; <italic>n</italic> = 16 CD [Crohn’s disease]—red circles, <italic>n</italic> = 7 CRC [colorectal cancer] —purple, <italic>n</italic> = 6 UC [ulcerative colitis [green], <italic>n</italic> = 9 HC [healthy control individuals] —light blue, <italic>n</italic> = 7 UTI [urinary tract infection] – orange circles and <italic>n</italic> = 3 Lab [laboratory] strains—black) on solid media under superoxide stress (LB agar containing 1 mM methyl viologen, pH 7.0) and their ability to survive and replicate within J774.A1 murine macrophages. Coefficient Rho (ρ) = 0.44; two-sided <italic>p</italic> = 0.0009.</p></caption><graphic xlink:href="pathogens-08-00074-g004"></graphic></fig><fig id="pathogens-08-00074-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Crohn’s disease mucosa-associated <italic>E. coli</italic> strains are able to grow within low-nutrient, acidic conditions characteristic of the macrophage phagolysosome environment. Comparison of CD mucosa-associated <italic>E. coli</italic> strains to non-intramacrophage replicating laboratory <italic>E. coli</italic> strains (EPI300, XL-1Blue and K-12) in low-nutrient culture medium (M9 minimal salts microbial growth medium supplemented with 0.1% w/v casamino acids, 100 mM Bis-Tris, 0.16% v/v glycerol and 10 μM magnesium chloride) at pH 7.0 (<bold>A</bold>) and pH 4.5 (<bold>B</bold>). All four CD <italic>E. coli</italic> strains showed tolerance over 8 h to low-nutrient M9 media, at pH 4.5. Laboratory <italic>E. coli</italic> strains were unable to grow well at pH 4.5 in M9 minimal media. Lines represent means of triplicate experimental cultures, with <italic>n</italic> = 3 replicates.</p></caption><graphic xlink:href="pathogens-08-00074-g005"></graphic></fig><fig id="pathogens-08-00074-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>CD mucosa-associated <italic>E. coli</italic> are unable to survive within <italic>Nfκb1</italic>-deficient murine bone-marrow derived macrophages (BMDM). Intra-macrophage replication of paradigm CD adherent, invasive <italic>E. coli</italic> HM605 (<bold>A</bold>) and LF82 (<bold>B</bold>) was significantly reduced within <italic>Nfκb1<sup>-/-</sup></italic> BMDM compared with those from C57BL/6 mice as determined by gentamicin protection assay. Data are expressed as relative fold change [mean ± SD] of recovered intra-macrophage bacteria 6 h post-infection compared to the number of viable colony-forming units (cfu) obtained immediately after a 1-h gentamicin treatment step (i.e., 3 h post-infection). Data obtained from differentiated BMDMs obtained from bone progenitor cells from four C57BL/6 mice (two male, two female); and four <italic>Nfκb1<sup>-/-</sup></italic> transgenic mice (one male, three female). Significant differences compared to C57BL/6 BMDMs ***<italic>p</italic> < 0.001, unpaired t-test.</p></caption><graphic xlink:href="pathogens-08-00074-g006"></graphic></fig><fig id="pathogens-08-00074-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>The effect of hydrocortisone on survival and replication of CD mucosa-associated <italic>E. coli</italic> HM605 within macrophages. J774A.1 murine macrophages were pre-treated with hydrocortisone for 24 h prior to inoculation with intra-macrophage replicating CD colonic mucosa-associated <italic>E.coli</italic> HM605. Data are expressed as mean % intra-macrophage bacteria (± SEM) present at 6 h/3 h post-infection, as assessed using a gentamicin protection assay. Significant differences compared to vehicle-treated macrophages, *<italic>p</italic> < 0.05 and **<italic>p</italic> < 0.01; Kruskal‒Wallis non-parametric ANOVA: <italic>N</italic> = 4, <italic>n</italic> = 12.</p></caption><graphic xlink:href="pathogens-08-00074-g007"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Irlande (pays)</li><li>Royaume-Uni</li></country></list><tree><noCountry><name sortKey="Campbell, Barry J" sort="Campbell, Barry J" uniqKey="Campbell B" first="Barry J." last="Campbell">Barry J. Campbell</name><name sortKey="Duckworth, Carrie A" sort="Duckworth, Carrie A" uniqKey="Duckworth C" first="Carrie A." last="Duckworth">Carrie A. Duckworth</name><name sortKey="Pritchard, D Mark" sort="Pritchard, D Mark" uniqKey="Pritchard D" first="D. Mark" last="Pritchard">D. Mark Pritchard</name><name sortKey="Rhodes, Jonathan M" sort="Rhodes, Jonathan M" uniqKey="Rhodes J" first="Jonathan M." last="Rhodes">Jonathan M. Rhodes</name></noCountry><country name="Irlande (pays)"><noRegion><name sortKey="Tawfik, Ahmed" sort="Tawfik, Ahmed" uniqKey="Tawfik A" first="Ahmed" last="Tawfik">Ahmed Tawfik</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="Knight, Paul" sort="Knight, Paul" uniqKey="Knight P" first="Paul" last="Knight">Paul Knight</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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