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J. Biol. Chem., Vol. 279, Issue 35, 36426-36432, August 27, 2004

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Nucleotide-binding Oligomerization Domain Proteins Are Innate Immune Receptors for Internalized Streptococcus pneumoniae^*

Bastian Opitz, Anja Püschel, Bernd Schmeck, Andreas C. Hocke, Simone Rosseau, Sven Hammerschmidt, Ralf R. Schumann¶, Norbert Suttorp, and Stefan Hippenstiel||

From the Department of Internal Medicine/Infectious Diseases, Charité University Medicine Berlin, 1 Augustenburger Platz, 13353 Berlin, Germany, Research Center for Infectious Diseases, University of Würzburg, 11 Röntgenring, 97070 Würzburg, Germany, and ^¶Department of Microbiology and Hygiene, Charité University Medicine Berlin, 96 Dorotheenstrasse, 10117 Berlin, Germany

Streptococcus pneumoniae, the major cause of community-acquired pneumonia and bacterial meningitis, has been shown to transiently invade epithelial and endothelial cells. Innate immune receptors including Toll-like receptors recognize various pathogens, such as S. pneumoniae, by identifying conserved pathogen-associated molecular patterns. Recently, two members of a novel class of pattern recognition receptors, the cytosolic proteins nucleotide-binding oligomerization domain 1 (Nod1)/CARD4 and Nod2/CARD15, have been found to detect cell wall peptidoglycans. Here we tested the hypothesis that Nod proteins are involved in the intracellular recognition of pneumococci. Data indicate that pneumococci invade HEK293 cells. Genetic complementation studies in these cells demonstrate that NF-B activation induced by S. pneumoniae depends on Nod2. Moreover, intracellular transfection of inactivated pneumococci yielded similar effects, confirming the Nod2 dependence of NF-B activation by pneumococci in HEK293 cells. By dominant negative overexpression and small interfering RNA experiments, we show for the first time that interleukin-1 receptor-associated kinase participates in Nod2-dependent NF-B activation. Additionally, dominant negative interleukin-1 receptor-associated kinase 2, tumor necrosis factor receptor-associated factor 6, NF-B-inducing kinase, transforming growth factor--activated kinase-binding protein 2, and transforming growth factor--activated kinase 1 also inhibited Nod2-dependent NF-B activation. We finally demonstrate that in C57BL/6 mouse lung tissue in vivo as well as in the bronchial epithelial cell line BEAS-2B, Nod1 and Nod2 mRNA expressions were up-regulated after pneumococcal infection. Data presented suggest that Nod proteins contribute to innate immune recognition of S. pneumoniae. Furthermore, Rip-2 and members of the Toll-like receptor-signaling cascade are involved in the Nod2-dependent activation of NF-B induced by pneumococci.

Received for publication, April 7, 2004

^* This work was supported in part by grants from the Bundesministerium für Bildung und Forschung NBL3 (to S. H.) and CAP-NETZ (to N. S., R. R. S., and S. R.). 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.

^|| To whom correspondence should be addressed. Tel.: 49-30-450-553052; Fax: 49-30-450-553911; E-mail: stefan.hippenstiel{at}charite.de.

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