Toll-Like Receptor 9-Dependent Immune Activation by Unmethylated CpG Motifs in Aspergillus fumigatus DNA

Phagocytic defenses are critical for effective host defenses against the opportunistic fungal pathogen Aspergillus fumigatus. Previous studies found that following challenge with A. fumigatus, Toll-like receptor 9 (TLR9) knockout mice survived longer than wild-type mice. However, the mechanism respo...

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Bibliographic Details
Published in:Infection and Immunity 2008-05, Vol.76 (5), p.2123-2129
Main Authors: Ramirez-Ortiz, Zaida G, Specht, Charles A, Wang, Jennifer P, Lee, Chrono K, Bartholomeu, Daniella C, Gazzinelli, Ricardo T, Levitz, Stuart M
Format: Article
Language:English
Subjects:
Animals
Aspergillus fumigatus
Aspergillus fumigatus - immunology
Biological and medical sciences
Cell Line
Cells, Cultured
CpG Islands - immunology
Cytokines - biosynthesis
Dendritic Cells - immunology
DNA, Fungal - immunology
DNA, Fungal - metabolism
DNA-Cytosine Methylases - metabolism
Endonucleases - metabolism
Fundamental and applied biological sciences. Psychology
Fungal and Parasitic Infections
Humans
Mice
Mice, Inbred C57BL
Microbiology
Miscellaneous
Mycology
Oligodeoxyribonucleotides - immunology
Toll-Like Receptor 9 - deficiency
Toll-Like Receptor 9 - immunology
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Summary:Phagocytic defenses are critical for effective host defenses against the opportunistic fungal pathogen Aspergillus fumigatus. Previous studies found that following challenge with A. fumigatus, Toll-like receptor 9 (TLR9) knockout mice survived longer than wild-type mice. However, the mechanism responsible was not defined. Here we demonstrate that A. fumigatus contains unmethylated CpG sequences, the natural ligands for TLR9. A. fumigatus DNA and synthetic CpG-rich oligodeoxynucleotides (ODNs) containing sequences found in the A. fumigatus genome potently stimulated the production of proinflammatory cytokines in mouse bone marrow-derived dendritic cells (BMDCs) and human plasmacytoid dendritic cells. The response was decreased when the fungal DNA was treated with a CpG methylase or with CpG-specific endonucleases. A role for TLR9 was demonstrated as cytokine production was abolished in BMDCs from TLR9-deficient mice. Moreover, transfection of HEK293 cells with human TLR9 conferred responsiveness to synthetic CpG-rich ODNs containing sequences found in A. fumigatus DNA. Taken together, these data demonstrate that TLR9 detects A. fumigatus DNA, resulting in the secretion of proinflammatory cytokines, which may contribute to the immune response to the pathogen.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.00047-08