Toll-like receptor 9-dependent activation of myeloid dendritic cells by deoxynucleic acids from Candida albicans

Akiko Miyazato, Kiwamu Nakamura, Natsuo Yamamoto, Hector M Mora-Montes, Misuzu Tanaka, Yuzuru Abe, Daiki Tanno, Ken Inden, Xiao Gang, Keiko Ishii, Kiyoshi Takeda, Shizuo Akira, Shinobu Saijo, Yoichiro Iwakura, Yoshiyuki Adachi, Naohito Ohno, Kotaro Mitsutake, Neil A R Gow, Mitsuo Kaku, Kazuyoshi Kawakami

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)


The innate immune system of humans recognizes the human pathogenic fungus Candida albicans via sugar polymers present in the cell wall, such as mannan and beta-glucan. Here, we examined whether nucleic acids from C. albicans activate dendritic cells. C. albicans DNA induced interleukin-12p40 (IL-12p40) production and CD40 expression by murine bone marrow-derived myeloid dendritic cells (BM-DCs) in a dose-dependent manner. BM-DCs that lacked Toll-like receptor 4 (TLR4), TLR2, and dectin-1, which are pattern recognition receptors for fungal cell wall components, produced IL-12p40 at levels comparable to the levels produced by BM-DCs from wild-type mice, and DNA from a C. albicans pmr1Delta null mutant, which has a gross defect in mannosylation, retained the ability to activate BM-DCs. This stimulatory effect disappeared completely after DNase treatment. In contrast, RNase treatment increased production of the cytokine. A similar reduction in cytokine production was observed when BM-DCs from TLR9(-/-) and MyD88(-/-) mice were used. In a luciferase reporter assay, NF-kappaB activation was detected in TLR9-expressing HEK293T cells stimulated with C. albicans DNA. Confocal microscopic analysis showed similar localization of C. albicans DNA and CpG-oligodeoxynucleotide (CpG-ODN) in BM-DCs. Treatment of C. albicans DNA with methylase did not affect its ability to induce IL-12p40 synthesis, whereas the same treatment completely eliminated the ability of CpG-ODN to induce IL-12p40 synthesis. Finally, impaired clearance of this fungal pathogen was not found in the kidneys of TLR9(-/-) mice. These results suggested that C. albicans DNA activated BM-DCs through a TLR9-mediated signaling pathway using a mechanism independent of the unmethylated CpG motif.
Original languageEnglish
Pages (from-to)3056-3064
Number of pages9
JournalInfection and Immunity
Issue number7
Early online date11 May 2009
Publication statusPublished - Jul 2009


  • animals
  • antigens, CD40
  • Candida albicans
  • candidiasis
  • cell line
  • DNA, fungal
  • dendritic cells
  • female
  • humans
  • interleukin-12 subunit p40
  • kidney
  • male
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • myeloid differentiation factor 88
  • NF-kappa B
  • toll-like receptor 9


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