Characterization of Host and Bacterial Contributions to Lung Barrier Dysfunction Following Co-infection with 2009 Pandemic Influenza and Methicillin Resistant Staphylococcus aureus
Identifieur interne : 000E45 ( Pmc/Curation ); précédent : 000E44; suivant : 000E46Characterization of Host and Bacterial Contributions to Lung Barrier Dysfunction Following Co-infection with 2009 Pandemic Influenza and Methicillin Resistant Staphylococcus aureus
Auteurs : Michaela E. Nickol ; Justine Ciric ; Shane D. Falcinelli ; Daniel S. Chertow [États-Unis] ; Jason KindrachukSource :
- Viruses [ 1999-4915 ] ; 2019.
Abstract
Influenza viruses are a threat to global public health resulting in ~500,000 deaths each year. Despite an intensive vaccination program, influenza infections remain a recurrent, yet unsolved public health problem. Secondary bacterial infections frequently complicate influenza infections during seasonal outbreaks and pandemics, resulting in increased morbidity and mortality.
Url:
DOI: 10.3390/v11020116
PubMed: 30699912
PubMed Central: 6409999
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Characterization of Host and Bacterial Contributions to Lung Barrier Dysfunction Following Co-infection with 2009 Pandemic Influenza and Methicillin Resistant <italic>Staphylococcus aureus</italic></title><author><name sortKey="Nickol, Michaela E" sort="Nickol, Michaela E" uniqKey="Nickol M" first="Michaela E." last="Nickol">Michaela E. Nickol</name><affiliation><nlm:aff id="af1-viruses-11-00116">Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</nlm:aff></affiliation></author><author><name sortKey="Ciric, Justine" sort="Ciric, Justine" uniqKey="Ciric J" first="Justine" last="Ciric">Justine Ciric</name><affiliation><nlm:aff id="af1-viruses-11-00116">Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</nlm:aff></affiliation></author><author><name sortKey="Falcinelli, Shane D" sort="Falcinelli, Shane D" uniqKey="Falcinelli S" first="Shane D." last="Falcinelli">Shane D. Falcinelli</name><affiliation><nlm:aff id="af2-viruses-11-00116">Department of Microbiology and Immunology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;<email>shane_falcinelli@med.unc.edu</email></nlm:aff></affiliation></author><author><name sortKey="Chertow, Daniel S" sort="Chertow, Daniel S" uniqKey="Chertow D" first="Daniel S." last="Chertow">Daniel S. Chertow</name><affiliation><nlm:aff id="af3-viruses-11-00116">Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;<email>chertowd@cc.nih.gov</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-viruses-11-00116">Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD 20892</wicri:regionArea></affiliation></author><author><name sortKey="Kindrachuk, Jason" sort="Kindrachuk, Jason" uniqKey="Kindrachuk J" first="Jason" last="Kindrachuk">Jason Kindrachuk</name><affiliation><nlm:aff id="af1-viruses-11-00116">Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30699912</idno><idno type="pmc">6409999</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409999</idno><idno type="RBID">PMC:6409999</idno><idno type="doi">10.3390/v11020116</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000E45</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E45</idno><idno type="wicri:Area/Pmc/Curation">000E45</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000E45</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Characterization of Host and Bacterial Contributions to Lung Barrier Dysfunction Following Co-infection with 2009 Pandemic Influenza and Methicillin Resistant <italic>Staphylococcus aureus</italic></title><author><name sortKey="Nickol, Michaela E" sort="Nickol, Michaela E" uniqKey="Nickol M" first="Michaela E." last="Nickol">Michaela E. Nickol</name><affiliation><nlm:aff id="af1-viruses-11-00116">Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</nlm:aff></affiliation></author><author><name sortKey="Ciric, Justine" sort="Ciric, Justine" uniqKey="Ciric J" first="Justine" last="Ciric">Justine Ciric</name><affiliation><nlm:aff id="af1-viruses-11-00116">Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</nlm:aff></affiliation></author><author><name sortKey="Falcinelli, Shane D" sort="Falcinelli, Shane D" uniqKey="Falcinelli S" first="Shane D." last="Falcinelli">Shane D. Falcinelli</name><affiliation><nlm:aff id="af2-viruses-11-00116">Department of Microbiology and Immunology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;<email>shane_falcinelli@med.unc.edu</email></nlm:aff></affiliation></author><author><name sortKey="Chertow, Daniel S" sort="Chertow, Daniel S" uniqKey="Chertow D" first="Daniel S." last="Chertow">Daniel S. Chertow</name><affiliation><nlm:aff id="af3-viruses-11-00116">Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;<email>chertowd@cc.nih.gov</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-viruses-11-00116">Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD 20892</wicri:regionArea></affiliation></author><author><name sortKey="Kindrachuk, Jason" sort="Kindrachuk, Jason" uniqKey="Kindrachuk J" first="Jason" last="Kindrachuk">Jason Kindrachuk</name><affiliation><nlm:aff id="af1-viruses-11-00116">Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</nlm:aff></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</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>Influenza viruses are a threat to global public health resulting in ~500,000 deaths each year. Despite an intensive vaccination program, influenza infections remain a recurrent, yet unsolved public health problem. Secondary bacterial infections frequently complicate influenza infections during seasonal outbreaks and pandemics, resulting in increased morbidity and mortality. <italic>Staphylococcus aureus</italic>, including methicillin-resistant <italic>S. aureus</italic> (MRSA), is frequently associated with these co-infections, including the 2009 influenza pandemic. Damage to alveolar epithelium is a major contributor to severe influenza-bacterial co-infections and can result in gas exchange abnormalities, fluid leakage, and respiratory insufficiency. These deleterious manifestations likely involve both pathogen- and host-mediated mechanisms. However, there is a paucity of information regarding the mechanisms (pathogen- and/or host-mediated) underlying influenza-bacterial co-infection pathogenesis. To address this, we characterized the contributions of viral-, bacterial-, and host-mediated factors to the altered structure and function of alveolar epithelial cells during co-infection with a focus on the 2009 pandemic influenza (pdm2009) and MRSA. Here, we characterized pdm2009 and MRSA replication kinetics, temporal host kinome responses, modulation of MRSA virulence factors, and disruption of alveolar barrier integrity in response to pdm2009-MRSA co-infection. Our results suggest that alveolar barrier disruption during co-infection is mediated primarily through host response dysregulation, resulting in loss of alveolar barrier integrity.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Krammer, F" uniqKey="Krammer F">F. Krammer</name></author><author><name sortKey="Smith, G J D" uniqKey="Smith G">G.J.D. Smith</name></author><author><name sortKey="Fouchier, R A M" uniqKey="Fouchier R">R.A.M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Viruses</journal-id><journal-id journal-id-type="iso-abbrev">Viruses</journal-id><journal-id journal-id-type="publisher-id">viruses</journal-id><journal-title-group><journal-title>Viruses</journal-title></journal-title-group><issn pub-type="epub">1999-4915</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30699912</article-id><article-id pub-id-type="pmc">6409999</article-id><article-id pub-id-type="doi">10.3390/v11020116</article-id><article-id pub-id-type="publisher-id">viruses-11-00116</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Characterization of Host and Bacterial Contributions to Lung Barrier Dysfunction Following Co-infection with 2009 Pandemic Influenza and Methicillin Resistant <italic>Staphylococcus aureus</italic></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Nickol</surname><given-names>Michaela E.</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00116">1</xref></contrib><contrib contrib-type="author"><name><surname>Ciric</surname><given-names>Justine</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00116">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3554-226X</contrib-id><name><surname>Falcinelli</surname><given-names>Shane D.</given-names></name><xref ref-type="aff" rid="af2-viruses-11-00116">2</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-1675-1728</contrib-id><name><surname>Chertow</surname><given-names>Daniel S.</given-names></name><xref ref-type="aff" rid="af3-viruses-11-00116">3</xref><xref ref-type="aff" rid="af4-viruses-11-00116">4</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3305-7084</contrib-id><name><surname>Kindrachuk</surname><given-names>Jason</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00116">1</xref><xref rid="c1-viruses-11-00116" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-viruses-11-00116"><label>1</label>Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;<email>nickolm@myumanitoba.ca</email> (M.E.N.);<email>ciricj@myumanitoba.ca</email> (J.C.)</aff><aff id="af2-viruses-11-00116"><label>2</label>Department of Microbiology and Immunology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;<email>shane_falcinelli@med.unc.edu</email></aff><aff id="af3-viruses-11-00116"><label>3</label>Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;<email>chertowd@cc.nih.gov</email></aff><aff id="af4-viruses-11-00116"><label>4</label>Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA</aff><author-notes><corresp id="c1-viruses-11-00116"><label>*</label>Correspondence: <email>Jason.Kindrachuk@umanitoba.ca</email>; Tel.: +1-(204)-789-3807</corresp></author-notes><pub-date pub-type="epub"><day>29</day><month>1</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>2</month><year>2019</year></pub-date><volume>11</volume><issue>2</issue><elocation-id>116</elocation-id><history><date date-type="received"><day>16</day><month>1</month><year>2019</year></date><date date-type="accepted"><day>26</day><month>1</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>Influenza viruses are a threat to global public health resulting in ~500,000 deaths each year. Despite an intensive vaccination program, influenza infections remain a recurrent, yet unsolved public health problem. Secondary bacterial infections frequently complicate influenza infections during seasonal outbreaks and pandemics, resulting in increased morbidity and mortality. <italic>Staphylococcus aureus</italic>, including methicillin-resistant <italic>S. aureus</italic> (MRSA), is frequently associated with these co-infections, including the 2009 influenza pandemic. Damage to alveolar epithelium is a major contributor to severe influenza-bacterial co-infections and can result in gas exchange abnormalities, fluid leakage, and respiratory insufficiency. These deleterious manifestations likely involve both pathogen- and host-mediated mechanisms. However, there is a paucity of information regarding the mechanisms (pathogen- and/or host-mediated) underlying influenza-bacterial co-infection pathogenesis. To address this, we characterized the contributions of viral-, bacterial-, and host-mediated factors to the altered structure and function of alveolar epithelial cells during co-infection with a focus on the 2009 pandemic influenza (pdm2009) and MRSA. Here, we characterized pdm2009 and MRSA replication kinetics, temporal host kinome responses, modulation of MRSA virulence factors, and disruption of alveolar barrier integrity in response to pdm2009-MRSA co-infection. Our results suggest that alveolar barrier disruption during co-infection is mediated primarily through host response dysregulation, resulting in loss of alveolar barrier integrity.</p></abstract><kwd-group><kwd>influenza</kwd><kwd><italic>Staphylococcus aureus</italic></kwd><kwd>co-infection</kwd><kwd>2009 pandemic</kwd><kwd>alveolar epithelial cells</kwd><kwd>kinome</kwd><kwd>virulence factors</kwd><kwd>barrier function</kwd></kwd-group></article-meta></front><floats-group><fig id="viruses-11-00116-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Pathogen replication kinetics during bacterial infection and influenza-bacterial co-infection. A549 cells were infected with 2009 pandemic influenza (pdm2009) (MOI 0.1) or mock-infected, followed by MRSA infection 24 h later (MOI 0.1). (<bold>A</bold>) Alveolar epithelial cells were selectively lysed at the indicated time points, and CFU were quantified by standard bacterial plating. (<bold>B</bold>) Supernatants were harvested for isolation of viral RNA prior to quantification by RT-qPCR. Error bars represent SEM calculated from at least three biological replicates. Error bars for some of the time points are not visible due to the y-axis scale. No significant differences were found between groups as assessed by two-way ANOVA and significance testing by Tukey’s test.</p></caption><graphic xlink:href="viruses-11-00116-g001"></graphic></fig><fig id="viruses-11-00116-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Hierarchical clustering of temporal kinome responses of pdm2009, MRSA, and pdm2009 MRSA-infections in alveolar epithelial cells. Cells were plated 24 h prior to initial infection with pdm2009. Cells were infected or mock-infected with pdm2009 (MOI 0.1). Twenty four h post-pdm2009 infection, MRSA was added to cells at an MOI of 0.1. Cells were harvested for kinome analysis at the indicated time points. MRSA-alone-, pdm2009-alone-, and mock-infected time-matched samples were also collected at the indicated time points. <bold>A</bold>–<bold>C</bold> designate the three major dataset clusters as identified following hierarchical clustering.</p></caption><graphic xlink:href="viruses-11-00116-g002"></graphic></fig><fig id="viruses-11-00116-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Background-subtracted temporal kinome responses of pdm2009, MRSA, and pdm2009-MRSA infection. Mock-infected kinome responses were subtracted from the time-matched infected samples. Fold change phosphorylation values are plotted for all kinase recognition sequences on the kinome peptide arrays. Clustering analysis was performed with the Heatmapper software suite. Z-score values represent fold change differences in phosphorylation as compared to the time-matched mock-infected control cells.</p></caption><graphic xlink:href="viruses-11-00116-g003"></graphic></fig><fig id="viruses-11-00116-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>pdm2009-MRSA co-infection alters bacterial virulence factor expression in alveolar epithelial cells as compared to MRSA infection alone. MRSA virulence factor expression fold change values for co-infected samples relative to MRSA-alone-infected cells. Error bars represent SEM calculated from at least three biological replicates. Relative expression fold changes represent pdm2009-MRSA vs. MRSA infection alone and were calculated by the 2<sup>−ΔΔCT</sup> method. Comparison between groups was assessed by two-way ANOVA and significance testing by Tukey’s test, *<italic>p</italic> < 0.05.</p></caption><graphic xlink:href="viruses-11-00116-g004"></graphic></fig><fig id="viruses-11-00116-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>pdm2009-MRSA infection decreases barrier function in alveolar epithelial cells. Median resistance values have been plotted for all data points obtained during the experiment. Error bars have been removed to allow for clear visualization of all datasets, but were consistent across all biological replicates. A549 cells were plated 24 h prior to initial infection with pdm2009. Cells were infected or mock-infected with pdm2009, and MRSA was added to cells 24 h later. MRSA-alone, pdm2009-alone, 1% triton, and mock-infected time-matched conditions were also analyzed at the indicated time points. MOI values in parentheses signify the MRSA MOI utilized for infection. (<bold>A</bold>) Resistance data following infection with pdm2009 (MOI 0.1) and/or MRSA (MOI 0.1 or 0.01). (<bold>B</bold>) Resistance data following analysis with high MOI pdm2009 (MOI 0.1 or 3) and/or low MOI MRSA (MOI 0.01). Resistance data represent the median of at least three biological replicates with at least six technical replicates per sample per biological replicate. Arrows designate the addition of pdm2009 (first arrow) and MRSA or triton (second arrow) to the cells.</p></caption><graphic xlink:href="viruses-11-00116-g005"></graphic></fig><table-wrap id="viruses-11-00116-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">viruses-11-00116-t001_Table 1</object-id><label>Table 1</label><caption><p>Conservation of phosphorylation status between kinome analysis and phospho-Western blots. pdm2009-MRSA-infected A549 cell lysates 8 h post-MRSA infection were assessed by phospho-Western blot and by peptide kinome arrays.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Target</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Phosphosite</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Phospho-Western Blot (Fold Change)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Kinome Analysis (Fold Change)</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">PDGFRb</td><td align="center" valign="middle" rowspan="1" colspan="1">Y751</td><td align="center" valign="middle" rowspan="1" colspan="1">1.81</td><td align="center" valign="middle" rowspan="1" colspan="1">1.61</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Fyn</td><td align="center" valign="middle" rowspan="1" colspan="1">Y420</td><td align="center" valign="middle" rowspan="1" colspan="1">11.12</td><td align="center" valign="middle" rowspan="1" colspan="1">1.54</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">STAT5b</td><td align="center" valign="middle" rowspan="1" colspan="1">Y699</td><td align="center" valign="middle" rowspan="1" colspan="1">9.06</td><td align="center" valign="middle" rowspan="1" colspan="1">2.25</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Lyn</td><td align="center" valign="middle" rowspan="1" colspan="1">Y397</td><td align="center" valign="middle" rowspan="1" colspan="1">21.30</td><td align="center" valign="middle" rowspan="1" colspan="1">2.11</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Lck</td><td align="center" valign="middle" rowspan="1" colspan="1">Y394</td><td align="center" valign="middle" rowspan="1" colspan="1">14.42</td><td align="center" valign="middle" rowspan="1" colspan="1">2.03</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CREB</td><td align="center" valign="middle" rowspan="1" colspan="1">S133</td><td align="center" valign="middle" rowspan="1" colspan="1">2.00</td><td align="center" valign="middle" rowspan="1" colspan="1">2.54</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">β-catenin</td><td align="center" valign="middle" rowspan="1" colspan="1">Y654</td><td align="center" valign="middle" rowspan="1" colspan="1">8.97</td><td align="center" valign="middle" rowspan="1" colspan="1">2.39</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EGFR</td><td align="center" valign="middle" rowspan="1" colspan="1">Y1086</td><td align="center" valign="middle" rowspan="1" colspan="1">2.25</td><td align="center" valign="middle" rowspan="1" colspan="1">2.24</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Akt</td><td align="center" valign="middle" rowspan="1" colspan="1">S473</td><td align="center" valign="middle" rowspan="1" colspan="1">9.47</td><td align="center" valign="middle" rowspan="1" colspan="1">3.39</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">p38a</td><td align="center" valign="middle" rowspan="1" colspan="1">T180/Y182</td><td align="center" valign="middle" rowspan="1" colspan="1">2.65</td><td align="center" valign="middle" rowspan="1" colspan="1">2.13</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ERK1/2</td><td align="center" valign="middle" rowspan="1" colspan="1">T202/Y204; T185/Y187</td><td align="center" valign="middle" rowspan="1" colspan="1">29.17</td><td align="center" valign="middle" rowspan="1" colspan="1">2.62</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">GSK3a/b</td><td align="center" valign="middle" rowspan="1" colspan="1">S21/S9</td><td align="center" valign="middle" rowspan="1" colspan="1">1.75</td><td align="center" valign="middle" rowspan="1" colspan="1">1.73</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HSP60</td><td align="center" valign="middle" rowspan="1" colspan="1">S70</td><td align="center" valign="middle" rowspan="1" colspan="1">2.02</td><td align="center" valign="middle" rowspan="1" colspan="1">1.83</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" valign="middle" rowspan="1" colspan="1">S727</td><td align="center" valign="middle" rowspan="1" colspan="1">1.36</td><td align="center" valign="middle" rowspan="1" colspan="1">1.87</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Pyk2</td><td align="center" valign="middle" rowspan="1" colspan="1">Y402</td><td align="center" valign="middle" rowspan="1" colspan="1">1.76</td><td align="center" valign="middle" rowspan="1" colspan="1">2.53</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLCg1</td><td align="center" valign="middle" rowspan="1" colspan="1">Y783</td><td align="center" valign="middle" rowspan="1" colspan="1">1.67</td><td align="center" valign="middle" rowspan="1" colspan="1">1.31</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">c-Jun</td><td align="center" valign="middle" rowspan="1" colspan="1">S63</td><td align="center" valign="middle" rowspan="1" colspan="1">1.87</td><td align="center" valign="middle" rowspan="1" colspan="1">2.49</td></tr><tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">p53</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">S392</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.04</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.58</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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