Deletion of ripA alleviates suppression of the inflammasome and MAPK by Francisella tularensis

Max Tze Han Huang, Brittany L. Mortensen, Debra J. Taxman, Robin R. Craven, Sharon Taft-Benz, Todd M. Kijek, James R. Fuller, Beckley K. Davis, Irving Coy Allen, Willie June Brickey, Denis Gris, Haitao Wen, Thomas H. Kawula, Jenny Pan Yun Ting

Research output: Contribution to journalArticle

58 Scopus citations

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 (LVSDripA) provoked significant release of IL-1β, IL-18, and TNF-a 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.

Original languageEnglish (US)
Pages (from-to)5476-5485
Number of pages10
JournalJournal of Immunology
Volume185
Issue number9
DOIs
StatePublished - Nov 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Huang, M. T. H., Mortensen, B. L., Taxman, D. J., Craven, R. R., Taft-Benz, S., Kijek, T. M., Fuller, J. R., Davis, B. K., Allen, I. C., Brickey, W. J., Gris, D., Wen, H., Kawula, T. H., & Ting, J. P. Y. (2010). Deletion of ripA alleviates suppression of the inflammasome and MAPK by Francisella tularensis. Journal of Immunology, 185(9), 5476-5485. https://doi.org/10.4049/jimmunol.1002154