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Science 14 May 2004:
Vol. 304. no. 5673, pp. 1014 - 1018
DOI: 10.1126/science.1096158
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Reports

Regulation of Phagosome Maturation by Signals from Toll-Like Receptors

J. Magarian Blander and Ruslan Medzhitov*

In higher metazoans, phagocytosis is essential in host defense against microbial pathogens and in clearance of apoptotic cells. Both microbial and apoptotic cells are delivered on a common route from phagosomes to lysosomes for degradation. Here, we found that activation of the Toll-like receptor (TLR) signaling pathway by bacteria, but not apoptotic cells, regulated phagocytosis at multiple steps including internalization and phagosome maturation. Phagocytosis of bacteria was impaired in the absence of TLR signaling. Two modes of phagosome maturation were observed, constitutive and inducible; their differential engagement depended on the ability of the cargo to trigger TLR signaling.

Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

* To whom correspondence should be addressed. E-mail: ruslan.medzhitov{at}yale.edu

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Microbiology 152, 555-566
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The peptidoglycan recognition protein PGRP-SC1a is essential for Toll signaling and phagocytosis of Staphylococcus aureus in Drosophila.
L. S. Garver, J. Wu, and L. P. Wu (2006)
PNAS 103, 660-665
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Haemophilus ducreyi Targets Src Family Protein Tyrosine Kinases To Inhibit Phagocytic Signaling.
J. R. Mock, M. Vakevainen, K. Deng, J. L. Latimer, J. A. Young, N. S. C. van Oers, S. Greenberg, and E. J. Hansen (2005)
Infect. Immun. 73, 7808-7816
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Toll-Like Receptor 2 Deficiency Delays Pneumococcal Phagocytosis and Impairs Oxidative Killing by Granulocytes.
M. Letiembre, H. Echchannaoui, P. Bachmann, F. Ferracin, C. Nieto, M. Espinosa, and R. Landmann (2005)
Infect. Immun. 73, 8397-8401
   Abstract »    Full Text »    PDF »
Cutting Edge: MyD88 Controls Phagocyte NADPH Oxidase Function and Killing of Gram-Negative Bacteria.
F. S. Laroux, X. Romero, L. Wetzler, P. Engel, and C. Terhorst (2005)
J. Immunol. 175, 5596-5600
   Abstract »    Full Text »    PDF »
The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis.
P. B. Kang, A. K. Azad, J. B. Torrelles, T. M. Kaufman, A. Beharka, E. Tibesar, L. E. DesJardin, and L. S. Schlesinger (2005)
J. Exp. Med. 202, 987-999
   Abstract »    Full Text »    PDF »
B7-DC cross-linking restores antigen uptake and augments antigen-presenting cell function by matured dendritic cells.
S. Radhakrishnan, E. Celis, and L. R. Pease (2005)
PNAS 102, 11438-11443
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Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain.
L. M. Stuart, J. Deng, J. M. Silver, K. Takahashi, A. A. Tseng, E. J. Hennessy, R. A. B. Ezekowitz, and K. J. Moore (2005)
J. Cell Biol. 170, 477-485
   Abstract »    Full Text »    PDF »
Immunoregulation of Dendritic Cells.
M. A Wallet, P. Sen, and R. Tisch (2005)
Clin. Med. Res. 3, 166-175
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis Regulates CD1 Antigen Presentation Pathways through TLR-2.
C. Roura-Mir, L. Wang, T.-Y. Cheng, I. Matsunaga, C. C. Dascher, S. L. Peng, M. J. Fenton, C. Kirschning, and D. B. Moody (2005)
J. Immunol. 175, 1758-1766
   Abstract »    Full Text »    PDF »
LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide.
Y. Liu, S. Walter, M. Stagi, D. Cherny, M. Letiembre, W. Schulz-Schaeffer, H. Heine, B. Penke, H. Neumann, and K. Fassbender (2005)
Brain 128, 1778-1789
   Abstract »    Full Text »    PDF »
Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration.
S. Zareparsi, M. Buraczynska, K. E.H. Branham, S. Shah, D. Eng, M. Li, H. Pawar, B. M. Yashar, S. E. Moroi, P. R. Lichter, et al. (2005)
Hum. Mol. Genet. 14, 1449-1455
   Abstract »    Full Text »    PDF »
Modulation of TLR signalling by the C-terminal Src kinase (Csk) in macrophages.
D. Aki, R. Mashima, K. Saeki, Y. Minoda, M. Yamauchi, and A. Yoshimura (2005)
Genes Cells 10, 357-368
   Abstract »    Full Text »    PDF »
Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells.
P. Kleindienst, C. Wiethe, M. B. Lutz, and T. Brocker (2005)
J. Immunol. 174, 3941-3947
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Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity.
J. K. White, P. Mastroeni, J.-F. Popoff, C. A. W. Evans, and J. M. Blackwell (2005)
J. Leukoc. Biol. 77, 311-320
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Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt's Lymphoma.
C. A. Ogden, J. D. Pound, B. K. Batth, S. Owens, I. Johannessen, K. Wood, and C. D. Gregory (2005)
J. Immunol. 174, 3015-3023
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