Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection.
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 non-infectious insult to prevent inappropriate inflammation. Using the important obligate intracellular human pathogen Chlamy...
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Public Library of Science (PLoS)
2017-06-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006383&type=printable |
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| author | Steve J Webster Sven Brode Lou Ellis Timothy J Fitzmaurice Matthew J Elder Nelson O Gekara Panagiotis Tourlomousis Clare Bryant Simon Clare Ronnie Chee Hill J S Gaston Jane C Goodall |
| author_facet | Steve J Webster Sven Brode Lou Ellis Timothy J Fitzmaurice Matthew J Elder Nelson O Gekara Panagiotis Tourlomousis Clare Bryant Simon Clare Ronnie Chee Hill J S Gaston Jane C Goodall |
| author_sort | Steve J Webster |
| collection | DOAJ |
| description | 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 non-infectious 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-1β 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-1β 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-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. |
| format | Article |
| id | doaj-art-cc7ab21c35704bf99075bec68f1688a5 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2017-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-cc7ab21c35704bf99075bec68f1688a52025-08-20T03:24:29ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-06-01136e100638310.1371/journal.ppat.1006383Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection.Steve J WebsterSven BrodeLou EllisTimothy J FitzmauriceMatthew J ElderNelson O GekaraPanagiotis TourlomousisClare BryantSimon ClareRonnie CheeHill J S GastonJane C GoodallThe innate immune system is a critical component of host defence against microbial pathogens, but effective responses require an ability to distinguish between infectious and non-infectious 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-1β 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-1β 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-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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006383&type=printable |
| spellingShingle | Steve J Webster Sven Brode Lou Ellis Timothy J Fitzmaurice Matthew J Elder Nelson O Gekara Panagiotis Tourlomousis Clare Bryant Simon Clare Ronnie Chee Hill J S Gaston Jane C Goodall Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. PLoS Pathogens |
| title | Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. |
| title_full | Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. |
| title_fullStr | Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. |
| title_full_unstemmed | Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. |
| title_short | Detection of a microbial metabolite by STING regulates inflammasome activation in response to Chlamydia trachomatis infection. |
| title_sort | detection of a microbial metabolite by sting regulates inflammasome activation in response to chlamydia trachomatis infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1006383&type=printable |
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