1. Deletion of ripA alleviates suppression of the inflammasome and MAPK by Francisella tularensis
- Author
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Debra J. Taxman, Sharon Taft-Benz, Robin R. Craven, Willie June Brickey, Haitao Wen, Irving C. Allen, Beckley K. Davis, Jenny P.-Y. Ting, Max Tze Han Huang, Brittany L. Mortensen, Todd M. Kijek, James R. Fuller, Thomas H. Kawula, and Denis Gris
- Subjects
medicine.medical_treatment ,Immunology ,Blotting, Western ,Enzyme-Linked Immunosorbent Assay ,Biology ,Article ,Microbiology ,Tularemia ,Mice ,Immune system ,Bacterial Proteins ,medicine ,Immunology and Allergy ,Animals ,Humans ,Secretion ,Francisella tularensis ,Immune Evasion ,Inflammation ,Mice, Knockout ,Intracellular parasite ,Macrophages ,Inflammasome ,biology.organism_classification ,medicine.disease ,Mice, Inbred C57BL ,Cytokine ,Genes, Bacterial ,Cytokines ,Female ,Signal transduction ,Mitogen-Activated Protein Kinases ,medicine.drug ,Signal Transduction - Abstract
Francisella tularensis is a facultative intracellular pathogen and potential biothreat agent. Evasion of the immune response contributes to the extraordinary virulence of this organism although the mechanism is unclear. Whereas wild-type strains induced low levels of cytokines, an F. tularensis ripA deletion mutant (LVSΔripA) provoked significant release of IL-1β, IL-18, and TNF-α by resting macrophages. IL-1β and IL-18 secretion was dependent on inflammasome components pyrin-caspase recruitment domain/apoptotic speck-containing protein with a caspase recruitment domain and caspase-1, and the TLR/IL-1R signaling molecule MyD88 was required for inflammatory cytokine synthesis. Complementation of LVSΔripA with a plasmid encoding ripA restored immune evasion. Similar findings were observed in a human monocytic line. The presence of ripA nearly eliminated activation of MAPKs including ERK1/2, JNK, and p38, and pharmacologic inhibitors of these three MAPKs reduced cytokine induction by LVSΔripA. Animals infected with LVSΔripA mounted a stronger IL-1β and TNF-α response than that of mice infected with wild-type live vaccine strain. This analysis revealed novel immune evasive mechanisms of F. tularensis.
- Published
- 2010