Department of Microbiology and Immunology, Brain Korea 21 Program, Jeju National University School of Medicine, Jeju, Jeju-Do, South Korea.
PLoS One. 2012;7(6):e39042. doi: 10.1371/journal.pone.0039042. Epub 2012 Jun 18.
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.
恙虫病东方体是恙虫病的病原体，是一种必需的细胞内细菌，它从内体/吞噬体中逃逸，并在宿主细胞质中复制。恙虫病东方体感染诱导产生促炎介质，包括白细胞介素-1β（IL-1β），当细胞溶质刺激激活胱天蛋白酶-1 时，IL-1β主要由巨噬细胞分泌，在称为炎性体的复合物中，它是引发和维持炎症反应的关键因素。然而，恙虫病东方体感染后 IL-1β成熟的机制尚未确定。在这项研究中，我们表明，IL-1 受体信号对于宿主有效抵抗恙虫病东方体感染是必需的。活的恙虫病东方体，但不是热或 UV 失活的恙虫病东方体，通过主动细菌摄取和内体/吞噬体成熟来激活炎性体。此外，恙虫病东方体刺激的 IL-1β分泌和胱天蛋白酶-1 的激活依赖于 ASC 和胱天蛋白酶-1，因为 ASC 和胱天蛋白酶-1 缺陷型巨噬细胞中 IL-1β的产生受损，但在 Nlrp3、Nlrc4 和 Aim2 缺陷型巨噬细胞中不受影响。因此，活的恙虫病东方体触发 ASC 炎性体激活导致 IL-1β的产生，这是宿主有效防御的关键先天免疫反应。
