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Differential Roles of CD14 and Toll-like Receptors 4and 2 in Murine Acinetobacter Pneumonia

Laboratory of Experimental Internal Medicine, Department of Pathology, and Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands; Department of Immunology, The Scripps Research Institute, La Jolla, California; Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

Correspondence and requests for reprints should be addressed to Tom van der Poll, M.D., Ph.D., Laboratory of Experimental Internal Medicine Academic Medical Center, University of Amsterdam, Meibergdreef 9, G2-132, 1105 AZ Amsterdam, The Netherlands. E-mail: t.vanderpoll{at}amc.uva.nl

Rationale: Acinetobacter baumannii is an opportunistic bacterial pathogen that is increasingly associated with gram-negative nosocomial pneumonia, but the molecular mechanisms that play a role in innate defenses during A. baumannii infection have not been elucidated.

Objective: To gain first insight into the role of CD14 and Toll-like receptors 4 and 2 in host response to A. baumannii pneumonia.

Methods: Respective gene-deficient mice were intranasally infected with A. baumannii, and bacterial outgrowth, lung inflammation, and pulmonary cytokine/chemokine responses were determined. To study the importance of LPS in the inflammatory response, mice were also challenged with A. baumannii LPS.

Measurements and Main Results: Bacterial counts were increased in CD14 and Toll-like receptor 4 gene–deficient mice, and only these animals developed bacteremia. The pulmonary cytokine/chemokine response was impaired in Toll-like receptor 4 knockout mice and the onset of lung inflammation was delayed. In contrast, Toll-like receptor 2–deficient animals displayed an earlier cell influx into lungs combined with increased macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 concentrations, which was associated with accelerated elimination of bacteria from the pulmonary compartment. Neither CD14 nor Toll-like receptor 4 gene–deficient mice responded to intranasal administration of LPS, whereas Toll-like receptor 2 knockout mice were indistinguishable from wild-type animals.

Conclusions: Our results suggest that CD14 and Toll-like receptor 4 play a key role in innate sensing of A. baumannii via the LPS moiety, resulting in effective elimination of the bacteria from the lung, whereas Toll-like receptor 2 signaling seems to counteract the robustness of innate responses during acute A. baumannii pneumonia.

Key Words: Acinetobacter • bacterial pneumonia • inflammation • lipopolysaccharide • macrophage • Toll-like receptor

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