Abstract
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.
Highlights
The obligate intracellular pathogen Chlamydia trachomatis is a major cause of infectious disease world-wide and can initiate inflammatory pathology such as pelvic inflammatory disease, reactive arthritis and infectious blindness
Innate responses to bacterial infection such as Chlamydia trachomatis activate inflammasomes to enable the processing of IL-1β, IL-18 and the induction of an inflammatory form of cell death termed pyroptosis
A time course infection of bone marrow derived macrophages (BMDM) with C. trachomatis resulted in significant increases in IL-1β secretion as early as 8–10 hours post infection in wild-type and caspase-11 deficient but not caspase-1 deficient BMDM indicating that the non-canonical inflammasome was not required for IL-1β maturation in response to C. trachomatis infection (Fig 1A)
Summary
The obligate intracellular pathogen Chlamydia trachomatis is a major cause of infectious disease world-wide and can initiate inflammatory pathology such as pelvic inflammatory disease, reactive arthritis and infectious blindness (trachoma). Murine models of Chlamydia infection demonstrate that host inflammatory mediators, the inflammatory cytokine IL-1β, type-1 interferons, caspase-1 and caspase-11 account for a significant proportion of infection associated pathology [1,2,3]. The non-canonical inflammasome is essential for pyroptosis and IL-1β maturation in response to infection with certain gram-negative bacterial pathogens, or the delivery of cytoplasmic LPS, and occurs as a consequence of the caspase-11 dependent cleavage of gasdermin-D (GSDMD) [11, 12] and pannexin-1 [13]. Activation of the non-canonical inflammasome in response to bacterial pathogens can occur as a direct result of cytosolic invasion by bacteria that occurs during infection with Burkolderia thailandensis, resulting in a rapid execution of caspase-11 mediated pyroptosis, essential to host defence [14]. Non-canonical inflammasome activation can occur as a consequence of LPS being released from bacterial pathogen containing vacuoles (PV), via the action of Immune Related GTPases (IRG’s) and Guanylate Binding Proteins (GBP’s) [15]
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