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,
* Department of Immunology, University of Cape Town, Cape Town, South Africa;
Pasteur Institute, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 277, and
Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8603, Université Paris V, Paris, France;
Department of Immunology, Saga Medical School, Saga, Japan; and
¶ Institut Transgénose, Centre National de la Recherche Scientifique, Orléans, France
Endotoxin from Gram-negative bacteria bound to CD14 signals through
Toll-like receptor (TLR) 4, while components of Gram-positive bacteria,
fungi, and Mycobacterium tuberculosis (M.tb.)
preferentially use TLR2 signaling. We asked whether TLR4 plays any role
in host resistance to M.tb. infection in vivo.
Therefore, we infected the TLR4 mutant C3H/HeJ mice and their controls,
C3H/HeN mice, with M.tb. by aerosol. TLR4 mutant mice
had a reduced capacity to eliminate mycobacteria from the lungs, spread
the infection to spleen and liver, with 10–100 times higher CFU organ
levels than the wild-type mice and succumbed within 5–7 mo, whereas
most of the wild-type mice controlled infection and survived the
duration of the experiment. The lungs of TLR4 mutant mice showed
chronic pneumonia with increased neutrophil infiltration, reduced
macrophages recruitment, and abundant acid-fast bacilli. Furthermore,
the pulmonary expression of TNF-
, IL-12p40, and monocyte
chemoattractant protein 1 was significantly lower in C3H/HeJ
mice when compared with the wild-type controls. C3H/HeJ-derived
macrophages infected in vitro with M.tb. produced lower
levels of TNF-. Finally, the purified mycobacterial glycolipid,
phosphatidylinositol mannosides, induced signaling in both a TLR2- and
TLR4-dependent manner, thus suggesting that recognition of
phosphatidylinositol mannosides in vivo may influence the development
of protective immunity. In summary, macrophage recruitment and the
proinflammatory response to M.tb. are impaired in TLR4
mutant mice, resulting in chronic infection with impaired elimination
of mycobacteria. Therefore, TLR4 signaling is required to mount a
protective response during chronic M.tb.
infection.
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T. Botha and B. Ryffel Reactivation of Latent Tuberculosis Infection in TNF-Deficient Mice J. Immunol., September 15, 2003; 171(6): 3110 - 3118. [Abstract] [Full Text] [PDF]
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C. Vignal, Y. Guerardel, L. Kremer, M. Masson, D. Legrand, J. Mazurier, and E. Elass Lipomannans, But Not Lipoarabinomannans, Purified from Mycobacterium chelonae and Mycobacterium kansasii Induce TNF-{alpha} and IL-8 Secretion by a CD14-Toll-Like Receptor 2-Dependent Mechanism J. Immunol., August 15, 2003; 171(4): 2014 - 2023. [Abstract] [Full Text] [PDF]
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K. A. Heldwein, M. D. Liang, T. K. Andresen, K. E. Thomas, A. M. Marty, N. Cuesta, S. N. Vogel, and M. J. Fenton TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG J. Leukoc. Biol., August 1, 2003; 74(2): 277 - 286. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, M. L. Schito, S. Hieny, and A. Sher Cutting Edge: In Vivo Induction of Integrated HIV-1 Expression by Mycobacteria Is Critically Dependent on Toll-Like Receptor 2 J. Immunol., August 1, 2003; 171(3): 1123 - 1127. [Abstract] [Full Text] [PDF]
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