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,¶
* Center for Pediatrics and Adolescent Medicine and
Department of Medicine, University Medical Centre Freiburg, Freiburg, Germany;
Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-positif, CNRS URA 2172, Paris, France;
Dipartimento di Patologia e Microbiologia Sperimentale, Università di Messina, Messina, Italy;
¶ Institut Cochin, Institut National de la Santé et de la Recherche Médicale Unité 567, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 810, University Descartes, Paris, France; and
|| Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655
Group B streptococcus (GBS) is the most important cause of neonatal sepsis, which is mediated in part by TLR2. However, GBS components that potently induce cytokines via TLR2 are largely unknown. We found that GBS strains of the same serotype differ in released factors that activate TLR2. Several lines of genetic and biochemical evidence indicated that lipoteichoic acid (LTA), the most widely studied TLR2 agonist in Gram-positive bacteria, was not essential for TLR2 activation. We thus examined the role of GBS lipoproteins in this process by inactivating two genes essential for bacterial lipoprotein (BLP) maturation: the prolipoprotein diacylglyceryl transferase gene (lgt) and the lipoprotein signal peptidase gene (lsp). We found that Lgt modification of the N-terminal sequence called lipobox was not critical for Lsp cleavage of BLPs. In the absence of lgt and lsp, lipoprotein signal peptides were processed by the type I signal peptidase. Importantly, both the 
lgt and the lsp mutant were impaired in TLR2 activation. In contrast to released factors, fixed lgt and lsp GBS cells exhibited normal inflammatory activity indicating that extracellular toxins and cell wall components activate phagocytes through independent pathways. In addition, the lgt mutant exhibited increased lethality in a model of neonatal GBS sepsis. Notably, LTA comprised little, if any, inflammatory potency when extracted from lgt GBS. In conclusion, mature BLPs, and not LTA, are the major TLR2 activating factors from GBS and significantly contribute to GBS sepsis.
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.
1 This work was supported in part by Grants He 3127/2-3 and He 3127/3-1 from Deutsche Forschungsgemeinschaft (to P.H.), Grant GPH 09 from the Institut Pasteur, Grant ANR-06-PATHO-001-01 from the Agence Nationale de la Recherche "ERA-NET PathoGenoMics," Grant LSHB-CT-2005-512061 from the Network of Excellence "Europathogenomics" (to P.T.-C.), and by Grants AI52455 and GM54060 from the National Institutes of Health (to D.T.G.).
2 P.H. and S.D. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Philipp Henneke, Center for Pediatrics and Adolescent Medicine, University Medical Centre Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany. E-mail address: philipp.henneke{at}uniklinik-freiburg.de
4 Abbreviations used in this paper: GBS, group B streptococcus; BLP, bacterial lipoprotein; LTA, lipoteichoic acid; Lgt, prolipoprotein diacylglyceryl transferase; Lsp, lipoprotein signal peptidase; Lmb, laminin-binding protein; MDP, muramyl dipeptide; PGN, peptidoglycan.
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