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Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection
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2017 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 13, no 6, e1006383Article in journal (Refereed) Published
Abstract [en]

The innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and noninfectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamydia trachomatis; an organism that causes significant immunopathology, we sought to determine critical host and pathogen factors that contribute to the induction of inflammasome activation. We assayed inflammasome activation by immunoblotting and ELISA to detect IL-1 beta processing and LDH release to determine pyroptosis. Using primary murine bone marrow derived macrophages or human monocyte derived dendritic cells, infected with live or attenuated Chlamydia trachomatis we report that the live organism activates both canonical and non-canonical inflammasomes, but only canonical inflammasomes controlled IL-1 beta processing which preceded pyroptosis. NADPH oxidase deficient macrophages were permissive to Chlamydia trachomatis replication and displayed elevated type-1 interferon and inflammasome activation. Conversely, attenuated, non-replicating Chlamydia trachomatis, primed but did not activate inflammasomes and stimulated reduced type-1 interferon responses. This suggested bacterial replication or metabolism as important factors that determine interferon responses and inflammasome activation. We identified STING but not cGAS as a central mediator of interferon regulated inflammasome activation. Interestingly, exogenous delivery of a Chlamydia trachomatis metabolite and STING ligand D cyclic di-AMP, recovered inflammasome activation to attenuated bacteria in a STING dependent manner thus indicating that a bacterial metabolite is a key factor initiating inflammasome activation through STING, independent of cGAS. These data suggest a potential mechanism of how the innate immune system can distinguish between infectious and non-infectious insult and instigate appropriate immune responses that could be therapeutically targeted.

Place, publisher, year, edition, pages
Public Library Science , 2017. Vol. 13, no 6, e1006383
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Microbiology in the medical area
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URN: urn:nbn:se:umu:diva-137812DOI: 10.1371/journal.ppat.1006383ISI: 000404511700013PubMedID: 28570638OAI: oai:DiVA.org:umu-137812DiVA: diva2:1128554
Available from: 2017-07-26 Created: 2017-07-26 Last updated: 2017-07-26Bibliographically approved

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Gekara, Nelson O.
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Molecular Infection Medicine Sweden (MIMS)Umeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Medicine)
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Microbiology in the medical area

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CiteExportLink to record
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Cite
Citation style
  • apa
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