Repression of Inflammasome by Francisella tularensis during Early Stages of Infection
| Autor: | Sally V. Catlett, Jonathan A. Harton, Meenakshi Malik, Elizabeth L. Westcott, Rachel J. Dotson, Sukalyani Banik, Seham M. Rabadi, Stephen Bradley, Chandra Shekhar Bakshi |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Inflammasomes
Interleukin-1beta Immunology Virulence complex mixtures Biochemistry Microbiology Proinflammatory cytokine Tularemia Mice AIM2 NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Francisella tularensis Molecular Biology Attenuated vaccine Cell Death biology Macrophages Interleukin-18 Nuclear Proteins Inflammasome Interferon-beta Cell Biology respiratory system bacterial infections and mycoses biology.organism_classification medicine.disease Virology Toll-Like Receptor 2 DNA-Binding Proteins Mice Inbred C57BL Toll-Like Receptor 4 Mutation bacteria Francisella Carrier Proteins Signal Transduction medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 288:23844-23857 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m113.490086 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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