TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia
Identifieur interne : 000364 ( Pmc/Checkpoint ); précédent : 000363; suivant : 000365TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia
Auteurs : Javeed A. Shah ; Robyn Emery ; Brian Lee ; Sambasivan Venkatasubramanian ; Jason D. Simmons ; Melanie Brown ; Chi F. Hung ; Jan M. Prins [Pays-Bas] ; Annelies Verbon [Pays-Bas] ; Thomas R. Hawn ; Shawn J. SkerrettSource :
- Mucosal immunology [ 1933-0219 ] ; 2019.
Abstract
Url:
DOI: 10.1038/s41385-019-0196-7
PubMed: 31462698
PubMed Central: 6824992
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">TOLLIP deficiency is associated with increased resistance to <italic>Legionella pneumophila</italic> pneumonia</title><author><name sortKey="Shah, Javeed A" sort="Shah, Javeed A" uniqKey="Shah J" first="Javeed A." last="Shah">Javeed A. Shah</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation><affiliation><nlm:aff id="A2">Veterans Affairs Puget Sound Health Care System, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Emery, Robyn" sort="Emery, Robyn" uniqKey="Emery R" first="Robyn" last="Emery">Robyn Emery</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Lee, Brian" sort="Lee, Brian" uniqKey="Lee B" first="Brian" last="Lee">Brian Lee</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Venkatasubramanian, Sambasivan" sort="Venkatasubramanian, Sambasivan" uniqKey="Venkatasubramanian S" first="Sambasivan" last="Venkatasubramanian">Sambasivan Venkatasubramanian</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Simmons, Jason D" sort="Simmons, Jason D" uniqKey="Simmons J" first="Jason D." last="Simmons">Jason D. Simmons</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Brown, Melanie" sort="Brown, Melanie" uniqKey="Brown M" first="Melanie" last="Brown">Melanie Brown</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Hung, Chi F" sort="Hung, Chi F" uniqKey="Hung C" first="Chi F." last="Hung">Chi F. Hung</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Prins, Jan M" sort="Prins, Jan M" uniqKey="Prins J" first="Jan M." last="Prins">Jan M. Prins</name><affiliation wicri:level="4"><nlm:aff id="A4">University of Amsterdam, Amsterdam, the Netherlands.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>University of Amsterdam, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName><orgName type="university">Université d'Amsterdam</orgName></affiliation></author><author><name sortKey="Verbon, Annelies" sort="Verbon, Annelies" uniqKey="Verbon A" first="Annelies" last="Verbon">Annelies Verbon</name><affiliation wicri:level="3"><nlm:aff id="A3">Erasmus Medical Center, Rotterdam, the Netherlands.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Erasmus Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Hawn, Thomas R" sort="Hawn, Thomas R" uniqKey="Hawn T" first="Thomas R." last="Hawn">Thomas R. Hawn</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Skerrett, Shawn J" sort="Skerrett, Shawn J" uniqKey="Skerrett S" first="Shawn J." last="Skerrett">Shawn J. Skerrett</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31462698</idno><idno type="pmc">6824992</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824992</idno><idno type="RBID">PMC:6824992</idno><idno type="doi">10.1038/s41385-019-0196-7</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000853</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000853</idno><idno type="wicri:Area/Pmc/Curation">000853</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000853</idno><idno type="wicri:Area/Pmc/Checkpoint">000364</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000364</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">TOLLIP deficiency is associated with increased resistance to <italic>Legionella pneumophila</italic> pneumonia</title><author><name sortKey="Shah, Javeed A" sort="Shah, Javeed A" uniqKey="Shah J" first="Javeed A." last="Shah">Javeed A. Shah</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation><affiliation><nlm:aff id="A2">Veterans Affairs Puget Sound Health Care System, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Emery, Robyn" sort="Emery, Robyn" uniqKey="Emery R" first="Robyn" last="Emery">Robyn Emery</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Lee, Brian" sort="Lee, Brian" uniqKey="Lee B" first="Brian" last="Lee">Brian Lee</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Venkatasubramanian, Sambasivan" sort="Venkatasubramanian, Sambasivan" uniqKey="Venkatasubramanian S" first="Sambasivan" last="Venkatasubramanian">Sambasivan Venkatasubramanian</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Simmons, Jason D" sort="Simmons, Jason D" uniqKey="Simmons J" first="Jason D." last="Simmons">Jason D. Simmons</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Brown, Melanie" sort="Brown, Melanie" uniqKey="Brown M" first="Melanie" last="Brown">Melanie Brown</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Hung, Chi F" sort="Hung, Chi F" uniqKey="Hung C" first="Chi F." last="Hung">Chi F. Hung</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Prins, Jan M" sort="Prins, Jan M" uniqKey="Prins J" first="Jan M." last="Prins">Jan M. Prins</name><affiliation wicri:level="4"><nlm:aff id="A4">University of Amsterdam, Amsterdam, the Netherlands.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>University of Amsterdam, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName><orgName type="university">Université d'Amsterdam</orgName></affiliation></author><author><name sortKey="Verbon, Annelies" sort="Verbon, Annelies" uniqKey="Verbon A" first="Annelies" last="Verbon">Annelies Verbon</name><affiliation wicri:level="3"><nlm:aff id="A3">Erasmus Medical Center, Rotterdam, the Netherlands.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Erasmus Medical Center, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Hawn, Thomas R" sort="Hawn, Thomas R" uniqKey="Hawn T" first="Thomas R." last="Hawn">Thomas R. Hawn</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author><author><name sortKey="Skerrett, Shawn J" sort="Skerrett, Shawn J" uniqKey="Skerrett S" first="Shawn J." last="Skerrett">Shawn J. Skerrett</name><affiliation><nlm:aff id="A1">Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</nlm:aff><wicri:noCountry code="subfield">Washington.</wicri:noCountry></affiliation></author></analytic><series><title level="j">Mucosal immunology</title><idno type="ISSN">1933-0219</idno><idno type="eISSN">1935-3456</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 id="P2"><italic>Legionella pneumophila</italic> (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires’ disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88-dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, <italic>Tollip</italic><sup>−/−</sup> mice demonstrated significantly fewer bacterial CFU and increased cytokine responses from BAL fluid. <italic>Tollip</italic><sup>−/−</sup> macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC <italic>ex vivo.</italic> This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16 – 0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. 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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101299742</journal-id><journal-id journal-id-type="pubmed-jr-id">35518</journal-id><journal-id journal-id-type="nlm-ta">Mucosal Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Mucosal Immunol</journal-id><journal-title-group><journal-title>Mucosal immunology</journal-title></journal-title-group><issn pub-type="ppub">1933-0219</issn><issn pub-type="epub">1935-3456</issn></journal-meta><article-meta><article-id pub-id-type="pmid">31462698</article-id><article-id pub-id-type="pmc">6824992</article-id><article-id pub-id-type="doi">10.1038/s41385-019-0196-7</article-id><article-id pub-id-type="manuscript">NIHMS1536669</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>TOLLIP deficiency is associated with increased resistance to <italic>Legionella pneumophila</italic> pneumonia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Javeed A.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Emery</surname><given-names>Robyn</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Brian</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Venkatasubramanian</surname><given-names>Sambasivan</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Simmons</surname><given-names>Jason D.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Melanie</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hung</surname><given-names>Chi F.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Prins</surname><given-names>Jan M.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Verbon</surname><given-names>Annelies</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hawn</surname><given-names>Thomas R.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Skerrett</surname><given-names>Shawn J.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Medicine, University of Washington School of Medicine, Seattle, Washington.</aff><aff id="A2"><label>2</label>Veterans Affairs Puget Sound Health Care System, Seattle, Washington.</aff><aff id="A3"><label>3</label>Erasmus Medical Center, Rotterdam, the Netherlands.</aff><aff id="A4"><label>4</label>University of Amsterdam, Amsterdam, the Netherlands.</aff><author-notes><fn fn-type="con" id="FN1"><p id="P1"><bold>Author Contributions.</bold> Study design: JAS, SJS. Manuscript preparation and editing: JAS, SJS, TRH. Data acquisition, analysis, and interpretation: JAS, RE, BL, SV, JDS, MB, CFH, SJS. Human cohort recruitment and data analysis: JAS, JMP, AV, TRH.</p></fn><corresp id="CR1"><underline>Corresponding Author</underline>: Javeed A. Shah, 750 Republican Street, Room E700, Seattle, WA 98109; <email>jashah@uw.edu</email>; Phone: 206-543-8728; Fax: 206-616-4898.</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>5</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>28</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="ppub"><month>11</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>28</day><month>2</month><year>2020</year></pub-date><volume>12</volume><issue>6</issue><fpage>1382</fpage><lpage>1390</lpage><pmc-comment>elocation-id from pubmed: 10.1038/s41385-019-0196-7</pmc-comment>
<permissions><license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms"><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link></license-p></license></permissions><abstract id="ABS1"><p id="P2"><italic>Legionella pneumophila</italic> (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires’ disease (LD). Lp activates multiple innate immune receptors, and TOLLIP dampens MyD88-dependent signaling and may influence susceptibility to LD. We evaluated the effect of TOLLIP on innate immunity, pneumonia severity, and LD susceptibility in mouse lungs and human populations. To accomplish this, we evaluated the effect of TOLLIP on lung-specific Lp control and immune response and associated a common functional TOLLIP variant with Lp-induced innate immune responses and LD susceptibility in humans. After aerosol Lp infection, <italic>Tollip</italic><sup>−/−</sup> mice demonstrated significantly fewer bacterial CFU and increased cytokine responses from BAL fluid. <italic>Tollip</italic><sup>−/−</sup> macrophages also suppressed intracellular Lp replication in a flagellin-independent manner. The presence of a previously characterized, functionally active SNP associated with decreased TOLLIP mRNA transcript in monocytes was associated with increased TNF and IL-6 secretion after Lp stimulation of PBMC <italic>ex vivo.</italic> This genotype was separately associated with decreased LD susceptibility (309 controls, 88 cases, p = 0.008, OR 0.36, 95% CI 0.16 – 0.76) in a candidate gene association study. These results suggest that TOLLIP decreases lung-specific TLR responses to increase LD susceptibility in human populations. Better understanding of TOLLIP may lead to novel immunomodulatory therapies.</p></abstract></article-meta></front><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1.</label><caption><title>TOLLIP-deficient mice demonstrate enhanced clearance of <italic>L. pneumophila</italic> (Lp) after aerosol infection.</title><p id="P35">Mice were infected with approximately 10<sup>6</sup> CFU WT Lp Philadelphia-1 strain and at 24, 72, and 144 hours post infection, lungs were harvested. A) Bacterial counts were measured by CFU on BCYE agar plates. B) Total polymorphonuclear cell counts from bronchoalveolar fluid. C) Total mononuclear cells from bronchoalveolar fluid samples. D) Hematoxylin and eosin staining of representative sections of D) WT and E) <italic>Tollip</italic><sup>−/−</sup> mouse lung 72hr after Lp aerosol infection. * p< 0.05, Student’s t-test, two sided. Error bars represent +/− SEM. N = 5 mice in each group at each time point. Data are representative of three independent experiments.</p></caption><graphic xlink:href="nihms-1536669-f0001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2.</label><caption><title>Cytokine Responses from WT and <italic>Tollip</italic><sup>−/−</sup> mice after <italic>L. pneumophila</italic> (Lp) aerosol infection.</title><p id="P36">Mice were infected with 10<sup>6</sup> CFU WT Lp Philadelphia-1 strain and after 24 hours, cytokine concentrations were measured from bronchoalveolar (BAL) fluid and serum. A) BAL cytokine concentrations measured by ELISA from WT and <italic>Tollip</italic><sup>−/−</sup> mice. * p < 0.05, Student’s two-sided t-test. B) BAL cytokines, measured by Luminex cytokine assay 24 hours after Lp aerosol infection. * p < 0.05, ** p < 0.01, *** p < 0.001, at 1% false discovery rate. Error bars represent +/− SEM. C) Serum cytokine concentrations measured by ELISA. * p < 0.05, Student’s two-sided t-test. Error bars represent +/− SEM. Data are representative of three independent experiments with N = 5 in each group.</p></caption><graphic xlink:href="nihms-1536669-f0002"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3.</label><caption><title>WT and <italic>Tollip</italic><sup>−/−</sup> Macrophage Cytokine Responses after TLR and NLR Stimulation.</title><p id="P37">Bone marrow-derived macrophages (BMDM) were isolated from WT and <italic>Tollip</italic><sup>−/−</sup> mice and stimulated with media, PAM3 (250ng/ml), a TLR 2/1 agonist, or LPS (10ng/ml), TLR4 agonist, for 24hr, and concentrations of A) TNF and B) IL-10 were measured from cellular supernatants. C) We stimulated mouse BMDM with LPS 100pg/ml for 2 hours, then stimulated overnight with C) media control or the NLRP3 ligand nigericin (100μg/ml) and D) NLRC4 ligand <italic>Salmonella</italic> flagellin (FliC, 100ng/ml) or bovine serum albumin (100ng/ml), coincubated with Lipofectamine 2000 to permit cytosolic translocation of each protein. IL-1β concentrations from cellular supernatants were measured by ELISA. Error bars are means ± SEM; statistical analyses were performed by paired t-tests using Prism 7.0e. * p < 0.05, Student’s two-sided t-test. The experiment shown is representative of three independent experiments, each conducted in triplicate.</p></caption><graphic xlink:href="nihms-1536669-f0003"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4.</label><caption><title>WT and <italic>Tollip</italic><sup>−/−</sup> Macrophage Cytokine Responses after <italic>L. pneumophila</italic> (Lp) Infection <italic>in vitro.</italic></title><p id="P38">Bone marrow-derived macrophages were isolated and infected with either negative control (mock), WT <italic>L. pneumophila</italic> (WT Lp), flagellin-deficient <italic>L. pneumophila</italic> (Δ<italic>flaA</italic> Lp), or <italic>dot</italic>-<italic>icm</italic>-locus-deficient <italic>L. pneumophila</italic> (Δ<italic>dotA</italic> Lp) on the JR32 background at MOI 10 overnight and A) TNF, B) IL-1β, and C) IL-6 concentrations were measured from cellular supernatants. * p < 0.05, Student’s two-sided t-test. Experiment shown is representative of three independent experiments, each performed in triplicate. Error bars represent +/− SEM of mean.</p></caption><graphic xlink:href="nihms-1536669-f0004"></graphic></fig><fig id="F5" orientation="portrait" position="float"><label>Figure 5.</label><caption><title>Intracellular <italic>L. pneumophila</italic> (Lp) Replication and Nonspecific Autophagy in WT and <italic>Tollip</italic><sup>−/−</sup> Macrophages.</title><p id="P39">A) Bone marrow-derived macrophages (BMDM) from WT and <italic>Tollip</italic><sup>−/−</sup> mice were infected with flagellin-deficient <italic>L. pneumophila</italic> (JR32 strain) expressing the luminescent <italic>lux</italic> gene. Relative luminescence was measured over time. B) Representative images depicting LC3+ organelles (<italic>green</italic>) and DAPI-stained nuclei (<italic>blue</italic>) from control (EV) or THP-1 cells with TOLLIP deleted via CRISPR-Cas9 gene editing (TOLLIP-KO) in RPMI supplemented with 10% FCS (ctrl) or EBSS (starve) for 4 hours. C) Tukey plot of the number of autophagosomes counted from 100 cells in EV and TOLLIP-KO cells in nutrient-enriched or starvation medium after 4 hours. Box demonstrates median and interquartile range of values. * p < 0.05, Mann-Whitney U-test, data is representative of three independent experiments. D) Western blot of THP-1 cells comparing LC3-II expression with β-actin as a control in TOLLIP-KO and control cell lines under nutrient-rich and starvation conditions, with or without chloroquine. E) Quantitative analysis of LC3-II expression, normalized to β-actin, in TOLLIP-deficient cells in control and TOLLIP-KO cells. Data are expressed as mean +/− SD of three separate experiments grouped together. * p < 0.05 by Student’s t test.</p></caption><graphic xlink:href="nihms-1536669-f0005"></graphic></fig><fig id="F6" orientation="portrait" position="float"><label>Figure 6.</label><caption><title>rs5743854 G/G allele is associated with increased proinflammatory cytokine secretion after <italic>L. pneumophila</italic> (Lp) infection.</title><p id="P40">Peripheral blood mononuclear cells were isolated from 62 healthy volunteers in Seattle and stimulated with media, WT Lp (MOI 1) or Δ<italic>flaA</italic> Lp (MOI 1) for 24 hours. Secreted TNF and IL-6 levels were measured in supernatants via ELISA. TNF responses after A) WT Lp or B) Δ<italic>flaA</italic> Lp infection, stratified by rs5743854 genotype. Number of individuals tested per genotype -- C/C = 34, G/C = 24, G/G = 4. IL-6 responses after C) WT Lp or D) Δ<italic>flaA</italic> Lp infection, stratified by rs5743854 genotype. Dots represent cytokine values for individual volunteers. Median value represented by red lines. * p < 0.05 by Mann-Whitney U-test in a recessive genetic model (GG vs (CC + CG)).</p></caption><graphic xlink:href="nihms-1536669-f0006"></graphic></fig><table-wrap id="T1" position="float" orientation="portrait"><label>Table 1.</label><caption><p id="P41">Distribution of TOLLIP rs5743854 G allele in Netherlands cohort.</p></caption><table frame="box" rules="all"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" valign="top" rowspan="1" colspan="1"></th><th align="left" valign="top" rowspan="1" colspan="1">Control</th><th align="left" valign="top" rowspan="1" colspan="1">Cases</th><th align="left" valign="middle" rowspan="1" colspan="1">P value</th><th align="left" valign="top" rowspan="1" colspan="1">Odds Ratio (95% CI)</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">N</td><td align="left" valign="top" rowspan="1" colspan="1">309</td><td align="left" valign="middle" rowspan="1" colspan="1">88</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Male, f<xref rid="TFN1" ref-type="table-fn">*</xref> (n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.51 (159)</td><td align="left" valign="top" rowspan="1" colspan="1">0.52 (44)</td><td align="left" valign="middle" rowspan="1" colspan="1">0.128</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Age (median, IQR)</td><td align="left" valign="top" rowspan="1" colspan="1">49.6 (35.2 – 56.1)</td><td align="left" valign="top" rowspan="1" colspan="1">64.7 (54.2 – 71.5)</td><td align="left" valign="top" rowspan="1" colspan="1">< 0.001</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Smoker, f<xref rid="TFN1" ref-type="table-fn">*</xref>(n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.31</td><td align="left" valign="top" rowspan="1" colspan="1">0.49</td><td align="left" valign="middle" rowspan="1" colspan="1">0.022</td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">COPD, f (n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.10 (24)</td><td align="left" valign="top" rowspan="1" colspan="1">0.07 (6)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Diabetes Mellitus, f (n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.04 (3)</td><td align="left" valign="top" rowspan="1" colspan="1">0.09 (8)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Cancer, f(n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.02 (2)</td><td align="left" valign="top" rowspan="1" colspan="1">0.04 (4)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Hx. Transplant, f(n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.02 (2)</td><td align="left" valign="top" rowspan="1" colspan="1">0 (0)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Autoimmune Dz, f(n)</td><td align="left" valign="top" rowspan="1" colspan="1">0 (0)</td><td align="left" valign="top" rowspan="1" colspan="1">0.02 (2)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Alcohol Use, f(n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.73 (61)</td><td align="left" valign="top" rowspan="1" colspan="1">0.35 (32)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Rs5743854 genotype</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1">0.008</td><td align="left" valign="top" rowspan="1" colspan="1">0.35 (0.16 – 0.76)<xref rid="TFN2" ref-type="table-fn">†</xref></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C/C f(n)</td><td align="left" valign="top" rowspan="1" colspan="1">0.32 (99)</td><td align="left" valign="top" rowspan="1" colspan="1">0.33 (29)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">G/C</td><td align="left" valign="top" rowspan="1" colspan="1">0.41 (127)</td><td align="left" valign="top" rowspan="1" colspan="1">0.52 (46)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">G/G</td><td align="left" valign="top" rowspan="1" colspan="1">0.27 (83)</td><td align="left" valign="top" rowspan="1" colspan="1">0.14 (12)</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><label>*</label><p id="P42">f=frequency</p></fn><fn id="TFN2"><label>†</label><p id="P43">recessive genetic model adjusted for gender, age, and comorbidities.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Pays-Bas</li></country><region><li>Hollande-Méridionale</li><li>Hollande-Septentrionale</li></region><settlement><li>Amsterdam</li><li>Rotterdam</li></settlement><orgName><li>Université d'Amsterdam</li></orgName></list><tree><noCountry><name sortKey="Brown, Melanie" sort="Brown, Melanie" uniqKey="Brown M" first="Melanie" last="Brown">Melanie Brown</name><name sortKey="Emery, Robyn" sort="Emery, Robyn" uniqKey="Emery R" first="Robyn" last="Emery">Robyn Emery</name><name sortKey="Hawn, Thomas R" sort="Hawn, Thomas R" uniqKey="Hawn T" first="Thomas R." last="Hawn">Thomas R. Hawn</name><name sortKey="Hung, Chi F" sort="Hung, Chi F" uniqKey="Hung C" first="Chi F." last="Hung">Chi F. Hung</name><name sortKey="Lee, Brian" sort="Lee, Brian" uniqKey="Lee B" first="Brian" last="Lee">Brian Lee</name><name sortKey="Shah, Javeed A" sort="Shah, Javeed A" uniqKey="Shah J" first="Javeed A." last="Shah">Javeed A. Shah</name><name sortKey="Simmons, Jason D" sort="Simmons, Jason D" uniqKey="Simmons J" first="Jason D." last="Simmons">Jason D. Simmons</name><name sortKey="Skerrett, Shawn J" sort="Skerrett, Shawn J" uniqKey="Skerrett S" first="Shawn J." last="Skerrett">Shawn J. Skerrett</name><name sortKey="Venkatasubramanian, Sambasivan" sort="Venkatasubramanian, Sambasivan" uniqKey="Venkatasubramanian S" first="Sambasivan" last="Venkatasubramanian">Sambasivan Venkatasubramanian</name></noCountry><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Prins, Jan M" sort="Prins, Jan M" uniqKey="Prins J" first="Jan M." last="Prins">Jan M. Prins</name></region><name sortKey="Verbon, Annelies" sort="Verbon, Annelies" uniqKey="Verbon A" first="Annelies" last="Verbon">Annelies Verbon</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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