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This Article Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0801497v1 183/1/670    most recent Alert me when this article is cited Alert me if a correction is posted 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 de C. Ventura, G. M. Articles by Si-Tahar, M. PubMed PubMed Citation Articles by de C. Ventura, G. M. Articles by Si-Tahar, M.

Lack of MyD88 Protects the Immunodeficient Host Against Fatal Lung Inflammation Triggered by the Opportunistic Bacteria Burkholderia cenocepacia

Grasiella M. de C. Ventura^*,, Viviane Balloy^*,, Reuben Ramphal, Huot Khun, Michel Huerre, Bernhard Ryffel^¶, Maria-Cristina M. Plotkowski^#, Michel Chignard^*, and Mustapha Si-Tahar^*,

^*Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France; Inserm, U874, Paris, France; Department of Medicine, University of Florida, Gainesville, FL 32610; Institut Pasteur, Unité de Recherche et d’Expertise Histotechnologie et Pathologie, Paris, France; ^¶University of Orleans and Centre National de la Recherehe Scientifique, Orleans, France; and ^#Microbiologia, Immunologia e Parasitologia, Universidade do Estado do Rio de Janeiro, Brazil

Burkholderia cenocepacia is an opportunistic pathogen of major concern for cystic fibrosis patients as well as immunocompromised cancer patients and transplant recipients. The mechanisms by which B. cenocepacia triggers a rapid health deterioration of the susceptible host have yet to be characterized. TLR and their key signaling intermediate MyD88 play a central role in the detection of microbial molecular patterns and in the initiation of an effective immune response. We performed a study to better understand the role of TLR-MyD88 signaling in B. cenocepacia-induced pathogenesis in the immunocompromised host, using an experimental murine model. The time-course of several dynamic parameters, including animal survival, bacterial load, and secretion of critical inflammatory mediators, was compared in infected and immunosuppressed wild-type and MyD88^–/– mice. Notably, when compared with wild-type mice, infected MyD88^–/– animals displayed significantly reduced levels of inflammatory mediators (including KC, TNF-, IL-6, MIP-2, and G-CSF) in blood and lung airspaces. Moreover, despite a higher transient bacterial load in the lungs, immunosuppressed mice deficient in MyD88 had an unexpected survival advantage. Finally, we showed that this B. cenocepacia-induced life-threatening infection of wild-type mice involved the proinflammatory cytokine TNF- and could be prevented by corticosteroids. Altogether, our findings demonstrate that a MyD88-dependent pathway can critically contribute to a detrimental host inflammatory response that leads to fatal pneumonia.

Address correspondence and reprint requests to Dr. M. Si-Tahar, Unité Défense Innée et Inflammation, Inserm U874, Institut Pasteur, 25 rue du Dr. Roux, Paris, France. E-mail address: sitahar{at}pasteur.fr.