Toll/IL-1R domain-containing adaptor protein (TIRAP) is a critical mediator of antibacterial defense in the lung against Klebsiella pneumoniae but not Pseudomonas aeruginosa

Samithamby Jeyaseelan, Scott K. Young, Masahiro Yamamoto, Patrick G. Arndt, Shizuo Akira, Jay K. Kolls, G. Scott Worthen

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Bacterial pneumonia is a leading cause of mortality and is associated with extensive neutrophil accumulation. Major pathogens associated with this disease include nonflagellated Klebsiella pneumoniae (Kp) and flagellated Pseudomonas aeruginosa (Pa). TLRs are essential for innate immune defense. TIRAP (Toll/HL-1R domain-containing adaptor protein) is an adaptor in TLR1, TLR2, TLR4, and TLR6 signaling, whereas MyB88 is an adaptor for all TLRs. However, the importance of TIRAP in pulmonary defense against Kp or Pa has not been examined. To demonstrate the role of TIRAP, TIRAP-deficient and wild-type littermates were intratracheally inoculated with Kp or Pa. We found that TIRAP-/- mice had substantial mortality, higher bacterial burden in the tongs, and enhanced dissemination following Kp challenge. Furthermore, Kp-indueed neutrophil sequestration, histopathology, and MIP-2, TNF-α, IL-6, and LIX (lipopolysaccharide-induced CXC chemokine) production were attenuated in the lungs of TIRAP-/- mice. In contrast, TIRAP is not required for Pa-induced mortality, pulmonary bacterial burden, bacterial dissemination, neutrophil accumulation, or histopathology, yet it is necessary for MIP-2, TNF-α, and IL-6 production, but not LIX production. However, both Kp- and Pa-induced neutrophil influxes are MyDSS dependent To determine the mechanisms associated with Pa-induced neutrophil accumulation, we inoculated mice with a flagellin C mutant of Pa (PaΔfliC) or purified flagellin, a TLR5 agonist. PaΔfliC-induced neutrophil sequestration and LIX expression are dependent on TIRAP, whereas flagellin-induced neutrophil influx and LIX expression are independent of TIRAP. These novel findings illustrate a pathogen-specific role for TIRAP in pulmonary defense and suggest that TLRS plays an essential role for Pa-induced neutrophil influx via LIX production.

Original languageEnglish (US)
Pages (from-to)538-547
Number of pages10
JournalJournal of Immunology
Volume177
Issue number1
DOIs
StatePublished - Jul 1 2006

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