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J. Biol. Chem., Vol. 279, Issue 47, 49315-49322, November 19, 2004

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The Development of Early Host Response to Pseudomonas aeruginosa Lung Infection Is Critically Dependent on Myeloid Differentiation Factor 88 in Mice^*

Melanie R. Power, Yongde Peng, Elana Maydanski, Jean S. Marshall¶, and Tong-Jun Lin, Supported by a New Investigator Award from the Canadian Institutes of Health Research and an investigatorship from the Isaac Walton Killam Health Center||**

From the Departments of Microbiology and Immunology, ^¶Pathology, and ^||Pediatrics, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada

Toll-like receptors (TLR) induce distinct patterns of host responses through myeloid differentiation factor 88 (MyD88)-dependent and/or -independent pathways, depending on the nature of the pathogen. Pseudomonas aeruginosa is a cause of serious lung infection in immunocompromised individuals and cystic fibrosis patients. The role of the TLR-MyD88 pathway in P. aeruginosa-induced lung infection in vivo was examined in this study. MyD88^-/- mice demonstrated an impaired clearance of P. aeruginosa from the lung. Little or no neutrophil recruitment was observed in the airways of MyD88^-/- mice following P. aeruginosa lung infection. This observation was associated with a reduced production of inflammatory mediators that affect neutrophil recruitment, including macrophage-inflammatory protein-2, tumor necrosis factor, and interleukin-1 in the airways of MyD88^-/- mice. Similarly, MyD88^-/- mice showed inhibited NF-B activation in the lung following P. aeruginosa infection. Interestingly, P. aeruginosa infection induced a 7.5-fold increase of TLR2 mRNA expression in the lungs of MyD88^+/+ mice. Furthermore, host responses to P. aeruginosa lung infection in TLR2^-/- and TLR4 mutant mice were partially inhibited compared with the responses of respective control mice. Taken together, our results indicate that the MyD88-dependent pathway is essential for the development of early host responses to P. aeruginosa infection, leading to the clearance of this bacterium, and that TLR2 and TLR4 are involved in this process.

Received for publication, February 25, 2004 , and in revised form, June 23, 2004.

^* This work was supported in part by grants from the Canadian Institutes of Health Research, Canadian Cystic Fibrosis Foundation, Nova Scotia Health Research Foundation, and Isaac Walton Killam Health Center. 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.

Supported by a studentship from the Isaac Walton Killam Health Center.

^** To whom correspondence should be addressed: Isaac Walton Killam Health Center, Dept. of Pediatrics, 5850 University Ave., Halifax, Nova Scotia B3J 3G9, Canada. Tel.: 902-470-8834; Fax: 902-470-7217; E-mail: tong-jun.lin{at}dal.ca.

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