Koo, Jung-EunHong, Hye-JinDearth, AndreaKobayashi, Koichi S.Koh, Young-Sang2013-03-182012Koo, Jung-Eun, Hye-Jin Hong, Andrea Dearth, Koichi S. Kobayashi, and Young-Sang Koh. 2012. Intracellular invasion of Orientia tsutsugamushi activates inflammasome in ASC-dependent manner. PLoS ONE 7(6): e39042.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:10436328Orientia 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.en-USBiologyImmunologyImmunityInnate ImmunityMicrobiologyInflammationHost-Pathogen InteractionMicrobial PathogensModel OrganismsAnimal ModelsMouseMedicineInfectious DiseasesBacterial DiseasesScrub TyphusJournal Article2013-03-1810.1371/journal.pone.0039042