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Pneumococcal Capsular Polysaccharide Is Immunogenic When Present on the Surface of Macrophages and Dendritic Cells: TLR4 Signaling Induced by a Conjugate Vaccine or by Lipopolysaccharide Is Conducive¹

Noam Cohen^*, Michal Stolarsky-Bennun^*, Hila Amir-Kroll^*, Raanan Margalit^*, Gabriel Nussbaum, Michal Cohen-Sfady^*, Meirav Pevsner-Fischer^*, Mati Fridkin, Herve Bercovier, Lea Eisenbach^*, Steffen Jung^* and Irun R. Cohen^2,*

^* Department of Immunology, Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel; Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel; and Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem

Previously, we reported that a peptide, p458, from the sequence of the mammalian 60-kDa heat shock protein (hsp60) molecule can serve as a carrier in conjugate vaccines with capsular polysaccharide (CPS) molecules of various bacteria. These conjugate vaccines were effective injected in PBS without added adjuvants. We now report that p458 conjugated to pneumococcal CPS type 4 (PS4) manifests innate adjuvant effects: it stimulated mouse macrophages to secrete IL-12 and induced the late appearance of PS4 on the macrophage surface in a TLR4-dependent manner; PS4 alone or conjugated to other carriers did not stimulate macrophages in vitro. The injection of macrophages manifesting PS4 on the surface into mice induced long-term resistance to lethal Streptococcus pneumoniae challenge. The TLR4 ligand LPS could also induce the late appearance on the surface of unconjugated PS4 and resistance to challenge in injected mice. Resistance was not induced by macrophages containing only internalized PS4 or by pulsed macrophages that had been lysed. Glutaraldehyde-fixed macrophages pulsed with PS4 did induce resistance to lethal challenge. Moreover, bone marrow-derived dendritic cells activated by LPS and pulsed with unconjugated CPS were also effective in inducing resistance to lethal challenge. Resistance induced by the PS4-pulsed bone marrow-derived dendritic cell was specific for pneumococcal CPS serotypes (type 3 or type 4) and was associated with the induction of CPS-specific IgG and IgM Abs.

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 by the Center for the Study of Emerging Diseases.

² Address correspondence and reprint requests to Dr. Irun R. Cohen, Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: irun.cohen{at}weizmann.ac.il

³ Abbreviations used in this paper: CPS, capsular polysaccharide; PS4, pneumococcal CPS type 4; PS3, pneumococcal CPS type 3; hsp60, 60-kDa heat shock protein.