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J. Biol. Chem., Vol. 283, Issue 29, 19879-19887, July 18, 2008

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Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9^*

Nina Gratz, Maria Siller, Barbara Schaljo, Zaid A. Pirzada¹, Irene Gattermeier, Ivo Vojtek, Carsten J. Kirschning, Hermann Wagner, Shizuo Akira^¶, Emmanuelle Charpentier², and Pavel Kovarik³

From the Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria, the Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, 81675 Munich, Germany, and the ^¶Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation of MAPKs and NF-B, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.

Received for publication, April 14, 2008

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^* This work was supported in part by Austrian Research Foundation Grants P16726 [GenBank] -B14, I27-B03, and SFB F28 (to P. K.) and Grant P17238 [GenBank] -B09 (to E. C.); the University Jubilee Foundation of the City of Vienna (Hochschuljubiläumsstiftung der Stadt Wien, HJST) Grant H-1020-2004 (to E. C.); and the European Science Foundation under the EUROCORES Programme Euro-DYNA through Contract ERAS-CT-2003-980409 of the European Commission, DG Research, FP6 (to the laboratory of P. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Recipient of a scholarship from the Higher Education Commission of Pakistan (laboratory of E. C.).

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² To whom correspondence may be addressed. Tel.: 431-4277-54608; Fax: 431-4277-9546; E-mail: emanuelle.charpentier{at}univie.ac.at. ³ To whom correspondence may be addressed. Tel.: 431-4277-54608; Fax: 431-4277-9546; E-mail: pavel.kovarik{at}univie.ac.at.

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