Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.
Identifieur interne : 000791 ( Main/Exploration ); précédent : 000790; suivant : 000792Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.
Auteurs : Patience T. Brace [Royaume-Uni] ; Liku B. Tezera [Royaume-Uni] ; Magdalena K. Bielecka [Royaume-Uni] ; Toby Mellows [Royaume-Uni] ; Diana Garay [Royaume-Uni] ; Shuye Tian [Australie] ; Lucinda Rand [Royaume-Uni] ; Justin Green [Royaume-Uni] ; Sanjay Jogai [Royaume-Uni] ; Andrew J. Steele [Royaume-Uni] ; Timothy M. Millar [Royaume-Uni] ; Tilman Sanchez-Elsner [Royaume-Uni] ; Jon S. Friedland [Royaume-Uni] ; Christopher G. Proud [Australie] ; Paul T. Elkington [Royaume-Uni]Source :
- PLoS pathogens [ 1553-7374 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Complexe-1 cible mécanistique de la rapamycine (MeSH), Complexes multiprotéiques (génétique), Complexes multiprotéiques (immunologie), Humains (MeSH), Macrophages (immunologie), Macrophages (microbiologie), Matrix metalloproteinase 1 (génétique), Matrix metalloproteinase 1 (immunologie), Mycobacterium tuberculosis (génétique), Mycobacterium tuberculosis (immunologie), Mycobacterium tuberculosis (physiologie), Phosphatidylinositol 3-kinases (génétique), Phosphatidylinositol 3-kinases (immunologie), Souris (MeSH), Sérine-thréonine kinases TOR (génétique), Sérine-thréonine kinases TOR (immunologie), Tuberculose pulmonaire (anatomopathologie), Tuberculose pulmonaire (génétique), Tuberculose pulmonaire (immunologie), Tuberculose pulmonaire (microbiologie).
- MESH :
- anatomopathologie : Tuberculose pulmonaire.
- génétique : Complexes multiprotéiques, Matrix metalloproteinase 1, Mycobacterium tuberculosis, Phosphatidylinositol 3-kinases, Sérine-thréonine kinases TOR, Tuberculose pulmonaire.
- immunologie : Complexes multiprotéiques, Macrophages, Matrix metalloproteinase 1, Mycobacterium tuberculosis, Phosphatidylinositol 3-kinases, Sérine-thréonine kinases TOR, Tuberculose pulmonaire.
- microbiologie : Macrophages, Tuberculose pulmonaire.
- physiologie : Mycobacterium tuberculosis.
- Animaux, Complexe-1 cible mécanistique de la rapamycine, Humains, Souris.
English descriptors
- KwdEn :
- Animals (MeSH), Humans (MeSH), Macrophages (immunology), Macrophages (microbiology), Matrix Metalloproteinase 1 (genetics), Matrix Metalloproteinase 1 (immunology), Mechanistic Target of Rapamycin Complex 1 (MeSH), Mice (MeSH), Multiprotein Complexes (genetics), Multiprotein Complexes (immunology), Mycobacterium tuberculosis (genetics), Mycobacterium tuberculosis (immunology), Mycobacterium tuberculosis (physiology), Phosphatidylinositol 3-Kinases (genetics), Phosphatidylinositol 3-Kinases (immunology), TOR Serine-Threonine Kinases (genetics), TOR Serine-Threonine Kinases (immunology), Tuberculosis, Pulmonary (genetics), Tuberculosis, Pulmonary (immunology), Tuberculosis, Pulmonary (microbiology), Tuberculosis, Pulmonary (pathology).
- MESH :
- chemical , genetics : Matrix Metalloproteinase 1, Multiprotein Complexes, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases.
- genetics : Mycobacterium tuberculosis, Tuberculosis, Pulmonary.
- immunology : Macrophages, Matrix Metalloproteinase 1, Multiprotein Complexes, Mycobacterium tuberculosis, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Tuberculosis, Pulmonary.
- microbiology : Macrophages, Tuberculosis, Pulmonary.
- pathology : Tuberculosis, Pulmonary.
- physiology : Mycobacterium tuberculosis.
- Animals, Humans, Mechanistic Target of Rapamycin Complex 1, Mice.
Abstract
Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.
DOI: 10.1371/journal.ppat.1006367
PubMed: 28570642
PubMed Central: PMC5453634
Affiliations:
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Brace</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Tezera, Liku B" sort="Tezera, Liku B" uniqKey="Tezera L" first="Liku B" last="Tezera">Liku B. Tezera</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Bielecka, Magdalena K" sort="Bielecka, Magdalena K" uniqKey="Bielecka M" first="Magdalena K" last="Bielecka">Magdalena K. Bielecka</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Mellows, Toby" sort="Mellows, Toby" uniqKey="Mellows T" first="Toby" last="Mellows">Toby Mellows</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Garay, Diana" sort="Garay, Diana" uniqKey="Garay D" first="Diana" last="Garay">Diana Garay</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Tian, Shuye" sort="Tian, Shuye" uniqKey="Tian S" first="Shuye" last="Tian">Shuye Tian</name><affiliation wicri:level="1"><nlm:affiliation>South Australian Health and Medical Research Institute, Adelaide, and School of Biological Sciences, University of Adelaide, Adelaide, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>South Australian Health and Medical Research Institute, Adelaide, and School of Biological Sciences, University of Adelaide, Adelaide</wicri:regionArea><wicri:noRegion>Adelaide</wicri:noRegion></affiliation></author><author><name sortKey="Rand, Lucinda" sort="Rand, Lucinda" uniqKey="Rand L" first="Lucinda" last="Rand">Lucinda Rand</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Infectious Diseases and Immunity, Imperial College London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Green, Justin" sort="Green, Justin" uniqKey="Green J" first="Justin" last="Green">Justin Green</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Infectious Diseases and Immunity, Imperial College London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Jogai, Sanjay" sort="Jogai, Sanjay" uniqKey="Jogai S" first="Sanjay" last="Jogai">Sanjay Jogai</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Steele, Andrew J" sort="Steele, Andrew J" uniqKey="Steele A" first="Andrew J" last="Steele">Andrew J. Steele</name><affiliation wicri:level="1"><nlm:affiliation>Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Millar, Timothy M" sort="Millar, Timothy M" uniqKey="Millar T" first="Timothy M" last="Millar">Timothy M. Millar</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Sanchez Elsner, Tilman" sort="Sanchez Elsner, Tilman" uniqKey="Sanchez Elsner T" first="Tilman" last="Sanchez-Elsner">Tilman Sanchez-Elsner</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author><author><name sortKey="Friedland, Jon S" sort="Friedland, Jon S" uniqKey="Friedland J" first="Jon S" last="Friedland">Jon S. Friedland</name><affiliation wicri:level="3"><nlm:affiliation>Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Infectious Diseases and Immunity, Imperial College London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Proud, Christopher G" sort="Proud, Christopher G" uniqKey="Proud C" first="Christopher G" last="Proud">Christopher G. Proud</name><affiliation wicri:level="1"><nlm:affiliation>South Australian Health and Medical Research Institute, Adelaide, and School of Biological Sciences, University of Adelaide, Adelaide, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>South Australian Health and Medical Research Institute, Adelaide, and School of Biological Sciences, University of Adelaide, Adelaide</wicri:regionArea><wicri:noRegion>Adelaide</wicri:noRegion></affiliation></author><author><name sortKey="Elkington, Paul T" sort="Elkington, Paul T" uniqKey="Elkington P" first="Paul T" last="Elkington">Paul T. Elkington</name><affiliation wicri:level="1"><nlm:affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Life Sciences, University of Southampton, Southampton</wicri:regionArea><wicri:noRegion>Southampton</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS pathogens</title><idno type="eISSN">1553-7374</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Humans (MeSH)</term><term>Macrophages (immunology)</term><term>Macrophages (microbiology)</term><term>Matrix Metalloproteinase 1 (genetics)</term><term>Matrix Metalloproteinase 1 (immunology)</term><term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term><term>Mice (MeSH)</term><term>Multiprotein Complexes (genetics)</term><term>Multiprotein Complexes (immunology)</term><term>Mycobacterium tuberculosis (genetics)</term><term>Mycobacterium tuberculosis (immunology)</term><term>Mycobacterium tuberculosis (physiology)</term><term>Phosphatidylinositol 3-Kinases (genetics)</term><term>Phosphatidylinositol 3-Kinases (immunology)</term><term>TOR Serine-Threonine Kinases (genetics)</term><term>TOR Serine-Threonine Kinases (immunology)</term><term>Tuberculosis, Pulmonary (genetics)</term><term>Tuberculosis, Pulmonary (immunology)</term><term>Tuberculosis, Pulmonary (microbiology)</term><term>Tuberculosis, Pulmonary (pathology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term><term>Complexes multiprotéiques (génétique)</term><term>Complexes multiprotéiques (immunologie)</term><term>Humains (MeSH)</term><term>Macrophages (immunologie)</term><term>Macrophages (microbiologie)</term><term>Matrix metalloproteinase 1 (génétique)</term><term>Matrix metalloproteinase 1 (immunologie)</term><term>Mycobacterium tuberculosis (génétique)</term><term>Mycobacterium tuberculosis (immunologie)</term><term>Mycobacterium tuberculosis (physiologie)</term><term>Phosphatidylinositol 3-kinases (génétique)</term><term>Phosphatidylinositol 3-kinases (immunologie)</term><term>Souris (MeSH)</term><term>Sérine-thréonine kinases TOR (génétique)</term><term>Sérine-thréonine kinases TOR (immunologie)</term><term>Tuberculose pulmonaire (anatomopathologie)</term><term>Tuberculose pulmonaire (génétique)</term><term>Tuberculose pulmonaire (immunologie)</term><term>Tuberculose pulmonaire (microbiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Matrix Metalloproteinase 1</term><term>Multiprotein Complexes</term><term>Phosphatidylinositol 3-Kinases</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tuberculose pulmonaire</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mycobacterium tuberculosis</term><term>Tuberculosis, Pulmonary</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Complexes multiprotéiques</term><term>Matrix metalloproteinase 1</term><term>Mycobacterium tuberculosis</term><term>Phosphatidylinositol 3-kinases</term><term>Sérine-thréonine kinases TOR</term><term>Tuberculose pulmonaire</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Complexes multiprotéiques</term><term>Macrophages</term><term>Matrix metalloproteinase 1</term><term>Mycobacterium tuberculosis</term><term>Phosphatidylinositol 3-kinases</term><term>Sérine-thréonine kinases TOR</term><term>Tuberculose pulmonaire</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Macrophages</term><term>Matrix Metalloproteinase 1</term><term>Multiprotein Complexes</term><term>Mycobacterium tuberculosis</term><term>Phosphatidylinositol 3-Kinases</term><term>TOR Serine-Threonine Kinases</term><term>Tuberculosis, Pulmonary</term></keywords><keywords scheme="MESH" qualifier="microbiologie" xml:lang="fr"><term>Macrophages</term><term>Tuberculose pulmonaire</term></keywords><keywords scheme="MESH" qualifier="microbiology" xml:lang="en"><term>Macrophages</term><term>Tuberculosis, Pulmonary</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Tuberculosis, Pulmonary</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Mycobacterium tuberculosis</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Mice</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Humains</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28570642</PMID><DateCompleted><Year>2017</Year><Month>09</Month><Day>21</Day></DateCompleted><DateRevised><Year>2019</Year><Month>02</Month><Day>02</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1553-7374</ISSN><JournalIssue CitedMedium="Internet"><Volume>13</Volume><Issue>6</Issue><PubDate><Year>2017</Year><Month>Jun</Month></PubDate></JournalIssue><Title>PLoS pathogens</Title><ISOAbbreviation>PLoS Pathog</ISOAbbreviation></Journal><ArticleTitle>Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.</ArticleTitle><Pagination><MedlinePgn>e1006367</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.ppat.1006367</ELocationID><Abstract><AbstractText>Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Brace</LastName><ForeName>Patience T</ForeName><Initials>PT</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-9146-4542</Identifier><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tezera</LastName><ForeName>Liku B</ForeName><Initials>LB</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-7898-6709</Identifier><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bielecka</LastName><ForeName>Magdalena K</ForeName><Initials>MK</Initials><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mellows</LastName><ForeName>Toby</ForeName><Initials>T</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-5241-0760</Identifier><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Garay</LastName><ForeName>Diana</ForeName><Initials>D</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-9450-8504</Identifier><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tian</LastName><ForeName>Shuye</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>South Australian Health and Medical Research Institute, Adelaide, and School of Biological Sciences, University of Adelaide, Adelaide, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rand</LastName><ForeName>Lucinda</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Green</LastName><ForeName>Justin</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jogai</LastName><ForeName>Sanjay</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steele</LastName><ForeName>Andrew J</ForeName><Initials>AJ</Initials><AffiliationInfo><Affiliation>Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Millar</LastName><ForeName>Timothy M</ForeName><Initials>TM</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4539-2445</Identifier><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sanchez-Elsner</LastName><ForeName>Tilman</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Friedland</LastName><ForeName>Jon S</ForeName><Initials>JS</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-7789-9649</Identifier><AffiliationInfo><Affiliation>Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Proud</LastName><ForeName>Christopher G</ForeName><Initials>CG</Initials><AffiliationInfo><Affiliation>South Australian Health and Medical Research Institute, Adelaide, and School of Biological Sciences, University of Adelaide, Adelaide, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Elkington</LastName><ForeName>Paul T</ForeName><Initials>PT</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-0390-0613</Identifier><AffiliationInfo><Affiliation>NIHR Biomedical Research Centre, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>MR/N006631/1</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>R33 AI102239</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>06</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS Pathog</MedlineTA><NlmUniqueID>101238921</NlmUniqueID><ISSNLinking>1553-7366</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D046912">Multiprotein Complexes</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.-</RegistryNumber><NameOfSubstance UI="D019869">Phosphatidylinositol 3-Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.24.7</RegistryNumber><NameOfSubstance UI="D020781">Matrix Metalloproteinase 1</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008264" MajorTopicYN="N">Macrophages</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000382" MajorTopicYN="N">microbiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020781" MajorTopicYN="N">Matrix Metalloproteinase 1</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D046912" MajorTopicYN="N">Multiprotein Complexes</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009169" MajorTopicYN="N">Mycobacterium tuberculosis</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014397" MajorTopicYN="N">Tuberculosis, Pulmonary</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000382" MajorTopicYN="N">microbiology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>11</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>04</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>6</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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Brace</name></noRegion><name sortKey="Bielecka, Magdalena K" sort="Bielecka, Magdalena K" uniqKey="Bielecka M" first="Magdalena K" last="Bielecka">Magdalena K. Bielecka</name><name sortKey="Elkington, Paul T" sort="Elkington, Paul T" uniqKey="Elkington P" first="Paul T" last="Elkington">Paul T. Elkington</name><name sortKey="Elkington, Paul T" sort="Elkington, Paul T" uniqKey="Elkington P" first="Paul T" last="Elkington">Paul T. Elkington</name><name sortKey="Friedland, Jon S" sort="Friedland, Jon S" uniqKey="Friedland J" first="Jon S" last="Friedland">Jon S. Friedland</name><name sortKey="Garay, Diana" sort="Garay, Diana" uniqKey="Garay D" first="Diana" last="Garay">Diana Garay</name><name sortKey="Green, Justin" sort="Green, Justin" uniqKey="Green J" first="Justin" last="Green">Justin Green</name><name sortKey="Jogai, Sanjay" sort="Jogai, Sanjay" uniqKey="Jogai S" first="Sanjay" last="Jogai">Sanjay Jogai</name><name sortKey="Mellows, Toby" sort="Mellows, Toby" uniqKey="Mellows T" first="Toby" last="Mellows">Toby Mellows</name><name sortKey="Millar, Timothy M" sort="Millar, Timothy M" uniqKey="Millar T" first="Timothy M" last="Millar">Timothy M. Millar</name><name sortKey="Rand, Lucinda" sort="Rand, Lucinda" uniqKey="Rand L" first="Lucinda" last="Rand">Lucinda Rand</name><name sortKey="Sanchez Elsner, Tilman" sort="Sanchez Elsner, Tilman" uniqKey="Sanchez Elsner T" first="Tilman" last="Sanchez-Elsner">Tilman Sanchez-Elsner</name><name sortKey="Steele, Andrew J" sort="Steele, Andrew J" uniqKey="Steele A" first="Andrew J" last="Steele">Andrew J. Steele</name><name sortKey="Tezera, Liku B" sort="Tezera, Liku B" uniqKey="Tezera L" first="Liku B" last="Tezera">Liku B. Tezera</name></country><country name="Australie"><noRegion><name sortKey="Tian, Shuye" sort="Tian, Shuye" uniqKey="Tian S" first="Shuye" last="Tian">Shuye Tian</name></noRegion><name sortKey="Proud, Christopher G" sort="Proud, Christopher G" uniqKey="Proud C" first="Christopher G" last="Proud">Christopher G. Proud</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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