Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria

Alexandra K. Kiemer, Ryan H. Senaratne, Jessica Hoppstädter, Britta Diesel, Lee W. Riley, Koichi Tabeta, Stefan Bauer, Bruce Beutler, Bruce L. Zuraw

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)29-45
Number of pages17
JournalJournal of Innate Immunity
Volume1
Issue number1
DOIs
StatePublished - Aug 2008

Fingerprint

Toll-Like Receptor 9
Macrophage Activation
Mycobacterium
Macrophages
DNA
Alveolar Macrophages
Mycobacterium bovis
Cytokines
Phosphorothioate Oligonucleotides
Bacteria
Wild Animals
Survival
Real-Time Polymerase Chain Reaction
Cell Survival
Messenger RNA
Infection

Keywords

  • Host defence
  • Inflammation, lung
  • Macrophages
  • Mycobacteria
  • Oligonucleotide
  • Pathogen-associated molecular patterns
  • Pathogenesis
  • Toll-like receptor
  • Tuberculosis
  • Virulence factors

ASJC Scopus subject areas

  • Immunology and Allergy

Cite this

Kiemer, A. K., Senaratne, R. H., Hoppstädter, J., Diesel, B., Riley, L. W., Tabeta, K., ... Zuraw, B. L. (2008). Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria. Journal of Innate Immunity, 1(1), 29-45. https://doi.org/10.1159/000142731

Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria. / Kiemer, Alexandra K.; Senaratne, Ryan H.; Hoppstädter, Jessica; Diesel, Britta; Riley, Lee W.; Tabeta, Koichi; Bauer, Stefan; Beutler, Bruce; Zuraw, Bruce L.

In: Journal of Innate Immunity, Vol. 1, No. 1, 08.2008, p. 29-45.

Research output: Contribution to journalArticle

Kiemer, AK, Senaratne, RH, Hoppstädter, J, Diesel, B, Riley, LW, Tabeta, K, Bauer, S, Beutler, B & Zuraw, BL 2008, 'Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria', Journal of Innate Immunity, vol. 1, no. 1, pp. 29-45. https://doi.org/10.1159/000142731
Kiemer AK, Senaratne RH, Hoppstädter J, Diesel B, Riley LW, Tabeta K et al. Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria. Journal of Innate Immunity. 2008 Aug;1(1):29-45. https://doi.org/10.1159/000142731
Kiemer, Alexandra K. ; Senaratne, Ryan H. ; Hoppstädter, Jessica ; Diesel, Britta ; Riley, Lee W. ; Tabeta, Koichi ; Bauer, Stefan ; Beutler, Bruce ; Zuraw, Bruce L. / Attenuated activation of macrophage TLR9 by DNA from virulent mycobacteria. In: Journal of Innate Immunity. 2008 ; Vol. 1, No. 1. pp. 29-45.
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