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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901033v1 183/10/6629    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Cai, S. Articles by Jeyaseelan, S. PubMed PubMed Citation Articles by Cai, S. Articles by Jeyaseelan, S.

Both TRIF- and MyD88-Dependent Signaling Contribute to Host Defense against Pulmonary Klebsiella Infection¹

Shanshan Cai,^* Sanjay Batra,^* Li Shen,^* Nobuko Wakamatsu,^* and Samithamby Jeyaseelan^2*

^*Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University, Baton Rouge, LA 70803; and Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112

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-, IL-6, KC, MIP-2, but not LIX, expression in the lungs. In addition, K. pneumoniae-induced late NF-B 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-, IL-6, KC, MIP-2, and LIX expression with almost no neutrophil influx in the lungs. In MyD88^–/– mice, K. pneumoniae-induced early NF-B 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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by a Research Grant RG-22442-N from the American Lung Association, Scientist Award YCSA-062466 from the Flight Attendant Medical Research Institute, and Grants R01 HL-091958 and R01 HL-091958S1 from the National Institutes of Health via ARRA (to S.J.).

² Address correspondence and reprint requests to Dr. Samithamby Jeyaseelan, Pathobiolgical Sciences, LSU, Baton Rouge, LA 70803. E-mail address: jey{at}lsu.edu

³ Abbreviations used in this paper: TIR, Toll/IL-1R; TIRAP, TIR domain-containing adaptor protein; TRIF, TIR domain-containing adaptor inducing IFN-β; TRAM, TRIF-related adaptor molecule; LIX, LPS-induced CXC chemokine; KC, keratinocyte cell-derived chemokine; AM, Alveolar macrophage; BP, blocking peptide; CP, control peptide; BALF, bronchoalveolar lavage fluid; WT, wild type.