Intracellular invasion of Orientia tsutsugamushi activates inflammasome in asc-dependent manner.
Orientia tsutsugamushi, a causative agent of scrub typhus, is an obligate intracellular bacterium, which escapes from the endo/phagosome and replicates in the host cytoplasm. O. tsutsugamushi infection induces production of pro-inflammatory mediators including interleukin-1β (IL-1β), which is secreted mainly from macrophages upon cytosolic stimuli by activating cysteine protease caspase-1 within a complex called the inflammasome, and is a key player in initiating and maintaining the inflammatory response. However, the mechanism for IL-1β maturation upon O. tsutsugamushi infection has not been identified. In this study, we show that IL-1 receptor signaling is required for efficient host protection from O. tsutsugamushi infection. Live Orientia, but not heat- or UV-inactivated Orientia, activates the inflammasome through active bacterial uptake and endo/phagosomal maturation. Furthermore, Orientia-stimulated secretion of IL-1β and activation of caspase-1 are ASC- and caspase-1- dependent since IL-1β production was impaired in Asc- and caspase-1-deficient macrophages but not in Nlrp3-, Nlrc4- and Aim2-deficient macrophages. Therefore, live O. tsutsugamushi triggers ASC inflammasome activation leading to IL-1β production, which is a critical innate immune response for effective host defense.
Department of Microbiology and Immunology, Brain Korea 21 Program, Jeju National University School of Medicine, Jeju, Jeju-Do, South Korea.
Jung-Eun
JE
Koo
Hye-Jin
HJ
Hong
Andrea
A
Dearth
Koichi S
KS
Kobayashi
Young-Sang
YS
Koh
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012285:Orientia tsutsugamushi / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012612:Scrub Typhus / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1; D020170:Caspase 1