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Science 291 (5508): 1544-1547

Copyright © 2001 by the American Association for the Advancement of Science

Induction of Direct Antimicrobial Activity Through Mammalian Toll-Like Receptors

Sybille Thoma-Uszynski,1* Steffen Stenger,2* Osamu Takeuchi,3 Maria Teresa Ochoa,1 Matthias Engele,2 Peter A. Sieling,1 Peter F. Barnes,4 Martin Röllinghoff,2 Pal L. Bölcskei,5 Manfred Wagner,5 Shizuo Akira,3 Michael V. Norgard,6 John T. Belisle,7 Paul J. Godowski,8 Barry R. Bloom,9 Robert L. Modlin1dagger

The mammalian innate immune system retains from Drosophila a family of homologous Toll-like receptors (TLRs) that mediate responses to microbial ligands. Here, we show that TLR2 activation leads to killing of intracellular Mycobacterium tuberculosis in both mouse and human macrophages, through distinct mechanisms. In mouse macrophages, bacterial lipoprotein activation of TLR2 leads to a nitric oxide-dependent killing of intracellular tubercle bacilli, but in human monocytes and alveolar macrophages, this pathway was nitric oxide-independent. Thus, mammalian TLRs respond (as Drosophila Toll receptors do) to microbial ligands and also have the ability to activate antimicrobial effector pathways at the site of infection.

1 Division of Dermatology, Department of Microbiology and Immunology and Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA.
2 Institute for Clinical Microbiology, Immunology and Hygiene, Universität Erlangen, 91054 Erlangen, Germany.
3 Department of Host Defense, Osaka University, Osaka, Japan.
4 Center for Pulmonary and Infectious Disease Control, Departments of Medicine, Cell Biology, and Immunology, University of Texas Health Center, Tyler, TX 75708-3154, USA.
5 Klinikum Nürnberg, Medical Clinic 3, 90419 Nürnberg, Germany.
6 University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
7 Department of Microbiology, Colorado State University, Fort Collins, CO 80523, USA.
8 Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
9 Office of the Dean, Harvard School of Public Health, Boston, MA 02115, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: rmodlin{at}

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Infect. Immun. 73, 6499-6507
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Effect of Deletion or Overexpression of the 19-Kilodalton Lipoprotein Rv3763 on the Innate Response to Mycobacterium tuberculosis.
G. R. Stewart, K. A. Wilkinson, S. M. Newton, S. M. Sullivan, O. Neyrolles, J. R. Wain, J. Patel, K.-L. Pool, D. B. Young, and R. J. Wilkinson (2005)
Infect. Immun. 73, 6831-6837
   Abstract »    Full Text »    PDF »
DNA Augments Antigenicity of Mycobacterial DNA-Binding Protein 1 and Confers Protection against Mycobacterium tuberculosis Infection in Mice.
S. Matsumoto, M. Matsumoto, K. Umemori, Y. Ozeki, M. Furugen, T. Tatsuo, Y. Hirayama, S. Yamamoto, T. Yamada, and K. Kobayashi (2005)
J. Immunol. 175, 441-449
   Abstract »    Full Text »    PDF »
Mycobacterium Tuberculosis Heat Shock Proteins Use Diverse Toll-like Receptor Pathways to Activate Pro-inflammatory Signals.
Y. Bulut, K. S. Michelsen, L. Hayrapetian, Y. Naiki, R. Spallek, M. Singh, and M. Arditi (2005)
J. Biol. Chem. 280, 20961-20967
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Regulated recruitment of DC-SIGN to cell-cell contact regions during zymosan-induced human dendritic cell aggregation.
G. de la Rosa, M. Yanez-Mo, R. Samaneigo, D. Serrano-Gomez, L. Martinez-Munoz, E. Fernandez-Ruiz, N. Longo, F. Sanchez-Madrid, A. L. Corbi, and P. Sanchez-Mateos (2005)
J. Leukoc. Biol. 77, 699-709
   Abstract »    Full Text »    PDF »
An Epidermal Barrier Wound Repair Pathway in Drosophila Is Mediated by grainy head.
K. A. Mace, J. C. Pearson, and W. McGinnis (2005)
Science 308, 381-385
   Abstract »    Full Text »    PDF »
Identification and Functional Characterization of Chicken Toll-Like Receptor 5 Reveals a Fundamental Role in the Biology of Infection with Salmonella enterica Serovar Typhimurium.
M. Iqbal, V. J. Philbin, G. S. K. Withanage, P. Wigley, R. K. Beal, M. J. Goodchild, P. Barrow, I. McConnell, D. J. Maskell, J. Young, et al. (2005)
Infect. Immun. 73, 2344-2350
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The physiological regulation of toll-like receptor expression and function in humans.
G. I Lancaster, Q. Khan, P. Drysdale, F. Wallace, A. E Jeukendrup, M. T Drayson, and M. Gleeson (2005)
J. Physiol. 563, 945-955
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A Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 Modulates the Inflammatory Response in Murine Sepsis.
S. Gibot, M.-N. Kolopp-Sarda, M.-C. Bene, P.-E. Bollaert, A. Lozniewski, F. Mory, B. Levy, and G. C. Faure (2004)
J. Exp. Med. 200, 1419-1426
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Long-Term Control of Mycobacterium bovis BCG Infection in the Absence of Toll-Like Receptors (TLRs): Investigation of TLR2-, TLR6-, or TLR2-TLR4-Deficient Mice.
D. Nicolle, C. Fremond, X. Pichon, A. Bouchot, I. Maillet, B. Ryffel, and V. J. F. Quesniaux (2004)
Infect. Immun. 72, 6994-7004
   Abstract »    Full Text »    PDF »
Prolonged Toll-Like Receptor Signaling by Mycobacterium tuberculosis and Its 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Induced Regulation of Selected Genes in Macrophages.
R. K. Pai, M. E. Pennini, A. A. R. Tobian, D. H. Canaday, W. H. Boom, and C. V. Harding (2004)
Infect. Immun. 72, 6603-6614
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Microarray Analysis Reveals Induction of Lipoprotein Genes in Mucoid Pseudomonas aeruginosa: Implications for Inflammation in Cystic Fibrosis.
A. M. Firoved, W. Ornatowski, and V. Deretic (2004)
Infect. Immun. 72, 5012-5018
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Mitogenicity of the Recombinant Mycobacterial 27-Kilodalton Lipoprotein Is Not Connected to Its Antiprotective Effect.
A.-H. Hovav, L. Davidovitch, G. Nussbaum, J. Mullerad, Y. Fishman, and H. Bercovier (2004)
Infect. Immun. 72, 3383-3390
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The Novel Cyclophilin-Binding Drug Sanglifehrin A Specifically Affects Antigen Uptake Receptor Expression and Endocytic Capacity of Human Dendritic Cells.
A. M. Woltman, N. Schlagwein, S. W. van der Kooij, and C. van Kooten (2004)
J. Immunol. 172, 6482-6489
   Abstract »    Full Text »    PDF »
IMMUNOLOGY: The Bell Tolls for Phagosome Maturation.
C. Watts (2004)
Science 304, 976-977
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Toll-Like Receptor 2 (TLR2)-Dependent-Positive and TLR2-Independent-Negative Regulation of Proinflammatory Cytokines by Mycobacterial Lipomannans.
V. J. Quesniaux, D. M. Nicolle, D. Torres, L. Kremer, Y. Guerardel, J. Nigou, G. Puzo, F. Erard, and B. Ryffel (2004)
J. Immunol. 172, 4425-4434
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Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice.
J. Branger, J. C. Leemans, S. Florquin, S. Weijer, P. Speelman, and T. van der Poll (2004)
Int. Immunol. 16, 509-516
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Toll-Like Receptor 2 Plays a Role in the Early Inflammatory Response to Murine Pneumococcal Pneumonia but Does Not Contribute to Antibacterial Defense.
S. Knapp, C. W. Wieland, C. van 't Veer, O. Takeuchi, S. Akira, S. Florquin, and T. van der Poll (2004)
J. Immunol. 172, 3132-3138
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The Arg753Gln polymorphism of the human Toll-like receptor 2 gene in tuberculosis disease.
A.C. Ogus, B. Yoldas, T. Ozdemir, A. Uguz, S. Olcen, I. Keser, M. Coskun, A. Cilli, and O. Yegin (2004)
Eur. Respir. J. 23, 219-223
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Toll-like Receptors Induce a Phagocytic Gene Program through p38.
S. E. Doyle, R. M. O'Connell, G. A. Miranda, S. A. Vaidya, E. K. Chow, P. T. Liu, S. Suzuki, N. Suzuki, R. L. Modlin, W.-C. Yeh, et al. (2004)
J. Exp. Med. 199, 81-90
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