Department of Medicine
Animals; Aspergillus fumigatus; Cell Line; Cells, Cultured; CpG Islands; Cytokines; DNA, Fungal; Dendritic Cells; Endonucleases; Humans; Mice; Mice, Inbred C57BL; Oligodeoxyribonucleotides; Site-Specific DNA Methyltransferase (Cytosine-Specific); Toll-Like Receptor 9
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Infect Immun. 2008 May;76(5):2123-9. Epub 2008 Mar 10. Link to article on publisher's site
Infection and immunity
Ramirez-Ortiz, Zaida G.; Specht, Charles A.; Wang, Jennifer P.; Lee, Chrono K.; Bartholomeu, Daniella C.; Gazzinelli, Ricardo T.; and Levitz, Stuart M., "Toll-like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA" (2008). Open Access Articles. 2016.