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Table of Contents
Vol. 1, No. 1, 2009
Issue release date: August 2008
Section title: Research Article
J Innate Immun 2009;1:29–45
(DOI:10.1159/000142731)

Attenuated Activation of Macrophage TLR9 by DNA from Virulent Mycobacteria

Kiemer A.K.a, c, e · Senaratne R.H.f · Hoppstädter J.a · Diesel B.a · Riley L.W.f · Tabeta K.d · Bauer S.b · Beutler B.d · Zuraw B.L.e, f
aPharmaceutical Biology, Saarland University, Saarbrücken, and bInstitute of Immunology, Philipps University Marburg, Marburg, Germany; cUniversity of California San Diego and dThe Scripps Research Institute, La Jolla, Calif., eVeterans Medical Research Foundation, San Diego, Calif. and fUC Berkeley, Berkeley, Calif., USA

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Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: April 10, 2008
Accepted: April 23, 2008
Published online: July 02, 2008
Issue release date: August 2008

Number of Print Pages: 17
Number of Figures: 7
Number of Tables: 0

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN

Abstract

Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitrodifferentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were markedly activated by DNA isolated from attenuated mycobacterial strains (H37Ra and Mycobacterium bovis BCG) as assessed by measuring cytokine expression by real-time PCR, whereas synthetic phosphorothioate-modified oligonucleotides had a much lower potency to activate human macrophages. Intracellular replication of H37Ra was higher in macrophages isolated from TLR9-deficient mice than in macrophages from wild-type mice, whereas H37Rv showed equal survival in cells from wild-type or mutant mice. Increased bacterial survival in mouse macrophages was accompanied by altered cytokine production as determined by Luminex bead assays. In vivo infection experiments also showed differential cytokine production in TLR9-deficient mice compared to wild-type animals. Both human monocyte-derived macrophages as well as human alveolar macrophages showed reduced activation upon treatment with DNA isolated from bacteria from virulent (M. bovis and H37Rv) compared to attenuated mycobacteria. We suggest attenuated TLR9 activation contributes to the insufficient host response against virulent mycobacteria.

© 2008 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: April 10, 2008
Accepted: April 23, 2008
Published online: July 02, 2008
Issue release date: August 2008

Number of Print Pages: 17
Number of Figures: 7
Number of Tables: 0

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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