Toll-Like Receptor 9-Dependent Activation of Myeloid Dendritic Cells by Deoxynucleic Acids from Candida albicans

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

来源：Infection and Immunity, 2009, 77(7): 3056-3064.

DOI：10.1128/IAI.00840-08

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 pmr1 Delta 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-kappa B 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.

• 出版日期2009-7
• 单位河北医科大学