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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Bibliographic Details
Published in:PLoS pathogens 2017-06, Vol.13 (6), p.e1006383-e1006383
Main Authors: Webster, Steve J, Brode, Sven, Ellis, Lou, Fitzmaurice, Timothy J, Elder, Matthew J, Gekara, Nelson O, Tourlomousis, Panagiotis, Bryant, Clare, Clare, Simon, Chee, Ronnie, Gaston, Hill J S, Goodall, Jane C
Format: Article
Language:English
Subjects:
Activation
AMP
Animals
Apoptosis
Arthritis
Assaying
Attenuation
Bacteria
Bacterial infections
Biology and Life Sciences
Bone marrow
Care and treatment
Cell death
Chlamydia
Chlamydia infections
Chlamydia Infections - immunology
Chlamydia Infections - microbiology
Chlamydia trachomatis
Chlamydia trachomatis - genetics
Chlamydia trachomatis - immunology
Chlamydia trachomatis - physiology
Colleges & universities
Condoms
Cyclic AMP - immunology
Dendritic cells
Dendritic Cells - immunology
Dendritic Cells - microbiology
Dosage and administration
Enzyme-linked immunosorbent assay
Female
Health aspects
Humans
Immune response
Immune system
Immunoblotting
Infections
Infectious diseases
Inflammasomes
Inflammasomes - immunology
Inflammation
Innate immunity
Interferon
Interferon Type I - genetics
Interferon Type I - immunology
Interleukin 1
Interleukin-1beta - genetics
Interleukin-1beta - immunology
Macrophages
Macrophages - immunology
Macrophages - microbiology
Male
Medicine and Health Sciences
Membrane Proteins - genetics
Membrane Proteins - immunology
Metabolism
Metabolites
Mice
Microorganisms
Monocytes
NAD(P)H oxidase
Nucleotidyltransferases - genetics
Nucleotidyltransferases - immunology
Oxidase
Pathogens
Physiological aspects
Proteins
Pyroptosis
Replication
Research and Analysis Methods
Rheumatology
Risk factors
Sexually transmitted diseases
STD
Veterinary medicine
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1006383