Document Detail


Repression of inflammasome by Francisella tularensis during early stages of infection.
MedLine Citation:
PMID:  23821549     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
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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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-07-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-08-19     Completed Date:  2013-11-26     Revised Date:  2014-08-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23844-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Carrier Proteins / metabolism
Cell Death
Francisella tularensis / immunology*
Humans
Inflammasomes / metabolism*
Interferon-beta / metabolism
Interleukin-18 / metabolism
Interleukin-1beta / metabolism
Macrophages / metabolism,  microbiology,  pathology
Mice
Mice, Inbred C57BL
Mutation / genetics
Nuclear Proteins / metabolism
Signal Transduction / immunology
Toll-Like Receptor 2 / metabolism
Toll-Like Receptor 4 / metabolism
Tularemia / immunology*,  microbiology*
Grant Support
ID/Acronym/Agency:
2P01AI056320/AI/NIAID NIH HHS; R21AI075250-01A2/AI/NIAID NIH HHS; R56AI090072-02/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Aim2 protein, mouse; 0/CIAS1 protein, mouse; 0/Carrier Proteins; 0/Inflammasomes; 0/Interleukin-18; 0/Interleukin-1beta; 0/Nuclear Proteins; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 4; 77238-31-4/Interferon-beta
Comments/Corrections

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