Deletion of ripA alleviates suppression of the inflammasome and MAPK by Francisella tularensis |
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Authors: | Huang Max Tze-Han Mortensen Brittany L Taxman Debra J Craven Robin R Taft-Benz Sharon Kijek Todd M Fuller James R Davis Beckley K Allen Irving Coy Brickey Willie June Gris Denis Wen Haitao Kawula Thomas H Ting Jenny Pan-Yun |
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Institution: | Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599-7290, USA. |
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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. |
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