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Infection and Immunity, July 2009, p. 3056-3064, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.00840-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Akiko Miyazato,1,8* Kiwamu Nakamura,1,{dagger} Natsuo Yamamoto,1 Héctor M. Mora-Montes,2 Misuzu Tanaka,3 Yuzuru Abe,3 Daiki Tanno,3 Ken Inden,1 Xiao Gang,2,{ddagger} Keiko Ishii,3 Kiyoshi Takeda,4 Shizuo Akira,5 Shinobu Saijo,6 Yoichiro Iwakura,6 Yoshiyuki Adachi,7 Naohito Ohno,7 Kotaro Mitsutake,8 Neil A. R. Gow,2 Mitsuo Kaku,1 and Kazuyoshi Kawakami3

Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai-shi, Miyagi 980-0574, Japan,1 School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom,2 Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryou-cho, Aoba-ku, Sendai-shi, Miyagi 980-8575, Japan,3 Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan,4 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Ymadaoka, Suita-shi, Osaka 565-0871, Japan,5 Center for Experimental Medicine, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,6 Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Science, School of Pharmacy, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392, Japan,7 Department of Infectious Diseases and Infection Control, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1298, and Core Research for Evolution Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan8

Received 7 July 2008/ Returned for modification 7 August 2008/ Accepted 7 April 2009

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 β-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.

* Corresponding author. Mailing address: Department of Infectious Diseases and Infection Control, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1298, Japan. Phone: 81-42-984-4392. Fax: 81-42-984-0280. E-mail: miyazato{at}saitama-med.ac.jp

{triangledown} Published ahead of print on 11 May 2009.

Editor: A. Casadevall

{dagger} Present address: Department of Medicine and Therapeutics, Control and Prevention of Infectious Diseases, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan.

{ddagger} Present address: Department of Laboratory Medicine, The 6th Affiliated Hospital, Sun-Yat Sen University, 26 Yuancunerheng Rd., Guangzhou 510655, China.

Infection and Immunity, July 2009, p. 3056-3064, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.00840-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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