Toll-like receptor 9-dependent activation of myeloid dendritic cells by Deoxynucleic acids from Candida albicans.
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.
Department of Infectious Diseases and Infection Control, Saitama International Medical Center, Saitama Medical University, Hidaka-shi, Saitama, Japan. miyazato@saitama-med.ac.jp
Akiko
A
Miyazato
Kiwamu
K
Nakamura
Natsuo
N
Yamamoto
Héctor M
HM
Mora-Montes
Misuzu
M
Tanaka
Yuzuru
Y
Abe
Daiki
D
Tanno
Ken
K
Inden
Xiao
X
Gang
Keiko
K
Ishii
Kiyoshi
K
Takeda
Shizuo
S
Akira
Shinobu
S
Saijo
Yoichiro
Y
Iwakura
Yoshiyuki
Y
Adachi
Naohito
N
Ohno
Kotaro
K
Mitsutake
Neil A R
NA
Gow
Mitsuo
M
Kaku
Kazuyoshi
K
Kawakami
D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology; D002460:Cell Line; D004271:DNA, Fungal / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D007668:Kidney / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D016328:NF-kappa B / Q000096:biosynthesis; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000276:immunology*
D019013:CD40 Antigens; D004271:DNA, Fungal; D053762:Interleukin-12 Subunit p40; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9