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Science 304 (5673): 1014-1018

Copyright © 2004 by the American Association for the Advancement of Science

Regulation of Phagosome Maturation by Signals from Toll-Like Receptors

J. Magarian Blander, and Ruslan Medzhitov*

Abstract: 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}

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Influenza Virus and Poly(I:C) Inhibit MHC Class I-Restricted Presentation of Cell-Associated Antigens Derived from Infected Dead Cells Captured by Human Dendritic Cells.
D. Frleta, C. I. Yu, E. Klechevsky, A.-L. Flamar, G. Zurawski, J. Banchereau, and A. K. Palucka (2009)
J. Immunol. 182, 2766-2776
   Abstract »    Full Text »    PDF »
Peritoneal macrophages are important for the early containment of Enterococcus faecium peritonitis in mice.
M. Leendertse, R. J.L. Willems, I. A.J. Giebelen, J. J.T.H. Roelofs, N. van Rooijen, M. J.M. Bonten, and T. van der Poll (2009)
Innate Immunity 15, 3-12
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Klebsiella pneumoniae Increases the Levels of Toll-Like Receptors 2 and 4 in Human Airway Epithelial Cells.
V. Regueiro, D. Moranta, M. A. Campos, J. Margareto, J. Garmendia, and J. A. Bengoechea (2009)
Infect. Immun. 77, 714-724
   Abstract »    Full Text »    PDF »
Real-time imaging of Leishmania mexicana-infected early phagosomes: a study using primary macrophages generated from green fluorescent protein-Rab5 transgenic mice.
C. Lippuner, D. Paape, A. Paterou, J. Brand, M. Richardson, A. J. Smith, K. Hoffmann, V. Brinkmann, C. Blackburn, and T. Aebischer (2009)
FASEB J 23, 483-491
   Abstract »    Full Text »    PDF »
Interaction analyses of human monocytes co-cultured with different forms of Aspergillus fumigatus.
J. Loeffler, Z. Haddad, M. Bonin, N. Romeike, M. Mezger, U. Schumacher, M. Kapp, F. Gebhardt, G.-U. Grigoleit, S. Stevanovic, et al. (2009)
J. Med. Microbiol. 58, 49-58
   Abstract »    Full Text »    PDF »
Toll-Like Receptor Prestimulation Increases Phagocytosis of Escherichia coli DH5{alpha} and Escherichia coli K1 Strains by Murine Microglial Cells.
S. Ribes, S. Ebert, D. Czesnik, T. Regen, A. Zeug, S. Bukowski, A. Mildner, H. Eiffert, U.-K. Hanisch, S. Hammerschmidt, et al. (2009)
Infect. Immun. 77, 557-564
   Abstract »    Full Text »    PDF »
Milk Fat Globule Epidermal Growth Factor-Factor VIII Is Down-Regulated in Sepsis via the Lipopolysaccharide-CD14 Pathway.
H. Komura, M. Miksa, R. Wu, S. M. Goyert, and P. Wang (2009)
J. Immunol. 182, 581-587
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An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity.
X.-L. Li, H. J. Ezelle, T.-J. Kang, L. Zhang, K. A. Shirey, J. Harro, J. D. Hasday, S. K. Mohapatra, O. R. Crasta, S. N. Vogel, et al. (2008)
PNAS 105, 20816-20821
   Abstract »    Full Text »    PDF »
Uncoupling of Induced Protein Processing from Maturation in Dendritic Cells Exposed to a Highly Antigenic Preparation from a Helminth Parasite.
F. A. Marshall and E. J. Pearce (2008)
J. Immunol. 181, 7562-7570
   Abstract »    Full Text »    PDF »
Phagocytosis and antigen presentation: a partnership initiated by Toll-like receptors.
J M. Blander (2008)
Ann Rheum Dis 67, iii44-iii49
   Abstract »    Full Text »    PDF »
CD14 Impairs Host Defense against Gram-Negative Sepsis Caused by Burkholderia pseudomallei in Mice.
W. J. Wiersinga, A. F. de Vos, C. W. Wieland, M. Leendertse, J. J. T. H. Roelofs, and T. van der Poll (2008)
The Journal of Infectious Disease 198, 1388-1397
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{beta}2-Integrin-induced p38 MAPK Activation Is a Key Mediator in the CD14/TLR4/MD2-dependent Uptake of Lipopolysaccharide by Hepatocytes.
M. J. Scott and T. R. Billiar (2008)
J. Biol. Chem. 283, 29433-29446
   Abstract »    Full Text »    PDF »
LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest.
S. K. Rampini, P. Selchow, C. Keller, S. Ehlers, E. C. Bottger, and P. Sander (2008)
Microbiology 154, 2991-3001
   Abstract »    Full Text »    PDF »
Importance of TLR2 in Early Innate Immune Response to Acute Pulmonary Infection with Porphyromonas gingivalis in Mice.
G. Hajishengallis, M. Wang, G. J. Bagby, and S. Nelson (2008)
J. Immunol. 181, 4141-4149
   Abstract »    Full Text »    PDF »

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