The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery.
BACKGROUND
Toll-like receptor (TLR) signalling is crucial for innate immune responses to infection. The involvement of TLRs in otitis media (OM), the most prevalent childhood disease in developed countries, has been implicated by studies in middle ear cell lines, by association studies of TLR-related gene polymorphisms, and by altered OM in mice bearing mutations in TLR genes. Activated TLRs signal via two alternative intracellular signaling molecules with differing effects; MyD88 (Myeloid differentiation primary response gene 88) inducing primarily interleukin expression and TRIF (Tir-domain-containing adaptor inducing interferon beta) mediating type I interferon (IFN) expression. We tested the hypothesis that TRIF and type I IFN signaling play a role in OM, using a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi). The ME inflammatory response to NTHi was examined in wild-type (WT) and TRIF-/- mice by qPCR, gene microarray, histopathology and bacterial culture.


RESULTS
Expression of TRIF mRNA was only modesty enhanced during OM, but both type I IFN signalling genes and type I IFN-inducible genes were significantly up-regulated in WT mice. TRIF-deficient mice showed reduced but more persistent mucosal hyperplasia and less leukocyte infiltration into the ME in response to NTHi infection than did WT animals. Viable bacteria could be cultured from MEs of TRIF-/- mice for much longer in the course of disease than was the case for middle ears of WT mice.


CONCLUSIONS
Our results demonstrate that activation of TRIF/type I IFN responses is important in both the pathogenesis and resolution of NTHi-induced OM.
Leichtle
Anke
A
Department of Surgery/Otolaryngology University of California, San Diego, 9500 Gilman Avenue, La Jolla, California 92093, USA. ankeleichtle@yahoo.de
Hernandez
Michelle
M
Pak
Kwang
K
Webster
Nicholas J
NJ
Wasserman
Stephen I
SI
Ryan
Allen F
AF
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006193:Haemophilus influenzae; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010033:Otitis Media / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse