| Mycobacterium tuberculosis Hip1 dampens macrophage pro-inflammatory responses by limiting TLR2 activation. | |
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MedLine Citation:
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PMID: 21947769 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Mycobacterium tuberculosis (Mtb) is a highly successful human pathogen that evades host innate immunity by interfering with macrophage functions. In addition to avoiding macrophage microbicidal activities, Mtb infection triggers secretion of pro-inflammatory cytokines and chemokines in macrophages. The levels of pro-inflammatory cytokines induced by clinical Mtb isolates are thought to play an important role in determining tuberculosis disease progression and severity, but the mechanisms by which Mtb modulates the magnitude of inflammatory responses remain unclear. Here we show that Mtb restricts robust macrophage activation and dampens pro-inflammatory responses through the cell envelope-associated serine hydrolase Hip1 (Hydrolase important for pathogenesis 1). By transcriptionally profiling macrophages infected with either wild type or hip1 mutant bacteria, we found that the hip1 mutant induced earlier and significantly higher levels of several pro-inflammatory cytokines and chemokines. We show that increased activation of TLR2- and MyD88- dependent signaling pathways mediates the enhanced cytokine secretion induced by the hip1 mutant. Thus Hip1 restricts the onset and magnitude of pro-inflammatory cytokines by limiting TLR2-dependent activation. We also show that Hip1 dampens TLR2-independent activation of the inflammasome and limits secretion of IL-18. Dampening of TLR2 signaling does not require viable Mtb or phagocytosis but does require Hip1 catalytic activity. We propose that Mtb restricts pro-inflammatory responses by masking cell surface interactions between TLR2 agonists on Mtb and TLR2 on macrophages. This strategy may allow Mtb to evade early detection by host immunity, delay the onset of adaptive immune responses and accelerate disease progression. |
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Authors:
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Ranjna Madan Lala; Katia Vitorello Peixoto; Fabio Re; Jyothi Rengarajan |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-26 |
Journal Detail:
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Title: Infection and immunity Volume: - ISSN: 1098-5522 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0246127 Medline TA: Infect Immun Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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