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Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection.

Authors: Cai, S  Batra, S  Shen, L  Wakamatsu, N  Jeyaseelan, S 
Citation: Cai S, etal., J Immunol. 2009 Nov 15;183(10):6629-38. Epub 2009 Oct 21.
Pubmed: (View Article at PubMed) PMID:19846873
DOI: Full-text: DOI:10.4049/jimmunol.0901033

Klebsiella pneumoniae causes extensive lung damage. TLR signaling involves adaptors TRIF and MyD88. However, the relative contribution of TRIF and MyD88 signaling in host defense against pulmonary K. pneumoniae infection has not been elucidated. Therefore, we investigated the role of TRIF and MyD88 in K. pneumoniae pneumonia. TRIF(-/-) mice infected with K. pneumoniae showed impaired survival and reduced bacterial clearance, neutrophil influx, histopathologic evidence of inflammation, and TNF-alpha, IL-6, KC, MIP-2, but not LIX, expression in the lungs. In addition, K. pneumoniae-induced late NF-kappaB activation and phosphorylation of MAPKs was attenuated in the lungs of TRIF(-/-) mice. However, MyD88(-/-) mice infected with K. pneumoniae showed a much more remarkable phenotype, including impaired survival and reduced bacterial clearance, histopathology, and TNF-alpha, IL-6, KC, MIP-2, and LIX expression with almost no neutrophil influx in the lungs. In MyD88(-/-) mice, K. pneumoniae-induced early NF-kappaB and MAPK activation in the lungs was also reduced. Furthermore, the role of MyD88 is dominant over TRIF because TRIF/MyD88 double knockout mice displayed a more pronounced phenotype than TRIF(-/-) mice. Moreover, human alveolar macrophages pretreated with MyD88 blocking peptide showed attenuated TNF-alpha, IL-6, and IL-8 expression. Also, C57BL/6 mice pretreated with MyD88 blocking peptide exhibited attenuation in K. pneumoniae-induced neutrophil influx and enhanced bacterial burden in the lungs and dissemination. Overall, this investigation provides new insights into the TRIF and MyD88 signaling triggered by pulmonary K. pneumoniae infection in the lungs and demonstrate the therapeutic potential of MyD88 in reducing excessive neutrophil influx in human disease during Gram-negative bacterial pneumonia.


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RGD Object Information
RGD ID: 4145490
Created: 2010-11-05
Species: All species
Last Modified: 2010-11-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.