Repression of Inflammasome by Francisella tularensis during Early Stages of Infection |
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Authors: | Rachel J Dotson Seham M Rabadi Elizabeth L Westcott Stephen Bradley Sally V Catlett Sukalyani Banik Jonathan A Harton Chandra Shekhar Bakshi Meenakshi Malik |
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Institution: | From the ‡Albany College of Pharmacy and Health Sciences, Albany, New York 12208.;§Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, and ;¶Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208 |
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Abstract: | Francisella tularensis is an important human pathogen responsible for causing tularemia. F. tularensis has long been developed as a biological weapon and is now classified as a category A agent by the Centers for Disease Control because of its possible use as a bioterror agent. F. tularensis represses inflammasome; a cytosolic multi-protein complex that activates caspase-1 to produce proinflammatory cytokines IL-1β and IL-18. However, the Francisella factors and the mechanisms through which F. tularensis mediates these suppressive effects remain relatively unknown. Utilizing a mutant of F. tularensis in FTL_0325 gene, this study investigated the mechanisms of inflammasome repression by F. tularensis. We demonstrate that muted IL-1β and IL-18 responses generated in macrophages infected with F. tularensis live vaccine strain (LVS) or the virulent SchuS4 strain are due to a predominant suppressive effect on TLR2-dependent signal 1. Our results also demonstrate that FTL_0325 of F. tularensis impacts proIL-1β expression as early as 2 h post-infection and delays activation of AIM2 and NLRP3-inflammasomes in a TLR2-dependent fashion. An enhanced activation of caspase-1 and IL-1β observed in FTL_0325 mutant-infected macrophages at 24 h post-infection was independent of both AIM2 and NLRP3. Furthermore, F. tularensis LVS delayed pyroptotic cell death of the infected macrophages in an FTL_0325-dependent manner during the early stages of infection. In vivo studies in mice revealed that suppression of IL-1β by FTL_0325 early during infection facilitates the establishment of a fulminate infection by F. tularensis. Collectively, this study provides evidence that F. tularensis LVS represses inflammasome activation and that F. tularensis-encoded FTL_0325 mediates this effect. |
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Keywords: | Bacterial Pathogenesis Cytokine Immunosuppression Inflammation Macrophages Francisella Il-1b Immune Subversion Inflammasome |
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