Intracellular invasion of Orientia tsutsugamushi activates inflammasome in asc-dependent manner

• Published in: PloS one Vol. 7; no. 6; p. e39042
• Main Authors: Koo, Jung-Eun, Hong, Hye-Jin, Dearth, Andrea, Kobayashi, Koichi S, Koh, Young-Sang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.06.2012; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins; Bacteria; Bacterial infections; Biology; Cancer; CARD Signaling Adaptor Proteins; Carrier Proteins - metabolism; Caspase; Caspase 1 - metabolism; Caspase-1; Cell activation; Cell Death - immunology; Cysteine proteinase; Cystine; Cytokines; Cytoplasm; Cytoskeletal Proteins - metabolism; Enzyme Activation; Enzymes; Gene expression; Health aspects; Humans; Immune response; Immune system; Immunology; Infection; Infections; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammatory response; Innate immunity; Interleukin; Interleukin 1; Interleukin 1 receptors; Interleukin-1beta - metabolism; Interleukins; Intracellular; Kinases; Legionella; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Maturation; Medical research; Medicine; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Orientia tsutsugamushi; Orientia tsutsugamushi - immunology; Pathogens; Pattern recognition; Phagocytosis - immunology; Phagosomes - metabolism; Polymerase chain reaction; Proteases; Proteins; Receptors, Interleukin-1 - metabolism; Rodents; Scrub typhus; Scrub Typhus - immunology; Scrub Typhus - metabolism; Signal Transduction; Signaling; Typhus; United States > US; South Korea; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039042

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.