Published ahead of print on October 6, 2005, doi:10.1164/rccm.200505-730OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 1, January 2006, 122-129
A more recent version of this article appeared on January 1, 2006
Submitted on May 10, 2005
Accepted on September 28, 2005
Differential Roles of CD14 and Toll-like Receptors 4 and 2 in Murine Acinetobacter pneumonia
Sylvia Knapp1, Catharina W Wieland1, Sandrine Florquin2, Ralph Pantophlet3, Lenie Dijkshoorn4, Ntambua Tshimbalanga1, Shizuo Akira5, and Tom van der Poll6*
1 Laboratory of Experimental Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands,
2 Academic Medical Center, Department of Pathology, University of Amsterdam, Amsterdam, The Netherlands,
3 Department of Immunology, The Scripps Research Institute, La Jolla, California, USA,
4 Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands,
5 Research Institute for Microbial Diseases, Osaka University, Osaka, Japan,
6 Laboratory of Experimental Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands; Academic Medical Center, Department of Infectious Diseases, Tropical Medicine and AIDS, University of Amsterdam, Amsterdam, The Netherlands
* To whom correspondence should be addressed. 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, Toll-like receptor 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 lipopolysaccharide in the inflammatory response, mice were also challenged with A. baumannii lipopolysaccharide.
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 knock-out 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 lipopolysaccharide, whereas Toll-like receptor 2 knock-out 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, LPS, macrophage, Toll-like receptor
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