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

• Published in: The Journal of immunology (1950) Vol. 185; no. 9; pp. 5476 - 5485
• Main 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
• Format: Journal Article
• Language: English
• Published: United States 01.11.2010
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; Blotting, Western; Cytokines - biosynthesis; Enzyme-Linked Immunosorbent Assay; Female; Francisella tularensis - genetics; Francisella tularensis - immunology; Francisella tularensis - pathogenicity; Genes, Bacterial - genetics; Genes, Bacterial - immunology; Humans; Immune Evasion - genetics; Immune Evasion - immunology; Inflammation - genetics; Inflammation - immunology; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - immunology; Signal Transduction - genetics; Signal Transduction - immunology; Tularemia - genetics; Tularemia - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002154

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.