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J. Biol. Chem., Vol. 279, Issue 38, 39798-39806, September 17, 2004

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Extracellular Mycobacterial DNA-binding Protein 1 Participates in Mycobacterium-Lung Epithelial Cell Interaction through Hyaluronic Acid^*

Keiko Aoki, Sohkichi Matsumoto, Yukio Hirayama, Takayuki Wada¶, Yuriko Ozeki||, Makoto Niki, Pilar Domenech**, Kiyoko Umemori, Saburo Yamamoto, Amao Mineda, Makoto Matsumoto¶¶, and Kazuo Kobayashi

From the Department of Host Defense, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan, the ^¶Osaka City Institute of Public Health and Environmental Sciences, Osaka 545-8585, Japan, ^||Osaka International College for Woman, 6-21-57 Tohdacho, Moriguchi, Osaka 570-8555, Japan, the ^**Tuberculosis Research Section, Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, Maryland 20852, the Department of Bacterial and Blood Products, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo 208-0011, the Department of Oral Histology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan, and the ^¶¶Otsuka Pharmaceutical Co., Ltd., Kagasuno 463-10 Kawauchi-cho, Tokushima 771-0192, Japan

Mycobacterium tuberculosis infects not only host macrophages but also nonprofessional phagocytes, such as alveolar epithelial cells. Glycosaminoglycans (GAGs) are considered as the component of mycobacterial adherence to epithelial cells. Here we show that extracellularly occurring mycobacterial DNA-binding protein 1 (MDP1) promotes mycobacterial infection to A549 human lung epithelial cells through hyaluronic acid (HA). Both surface plasmon resonance analysis and enzyme-linked immunosorbent assay revealed that MDP1 bound to HA, heparin, and chondroitin sulfate. Utilizing synthetic peptides, we next defined heparin-binding site of 20 amino acids from 31 to 50 of MDP1, which is responsible for the specific DNA-binding site of MDP1. MDP1 bound to A549 cells, and exogenous DNA and HA interfered with the interaction. The binding was also abolished by treatment of A549 cells with hyaluronidase, suggesting that HA participates in the MDP1-A549 cell interaction. Adherence of bacillus Calmette-Guérin (BCG) and M. tuberculosis to A549 cells was inhibited by addition of HA, DNA, and anti-MDP1 antibody, showing that MDP1 participates in the interaction between mycobacteria-alveolar epithelial cells. Simultaneous treatment of intratracheal BCG-infected mice with HA reduced the growth of BCG in vivo. Taken together, theses results suggest that HA participates in Mycobacterium-lung epithelium interaction and has potential for therapeutic and prophylactic interventions in mycobacterial infection.

Received for publication, March 9, 2004 , and in revised form, June 3, 2004.

^* This work was supported by grants from the Ministry of Health, Labour and Welfare (Research on Emerging and Re-emerging Infectious Diseases, Health Sciences Research Grants), The Japan Health Sciences Foundation, Ministry of Education Culture Sports Science and Technology, Inamori Foundation, Osaka City University (Urban Research Project), and The United States-Japan Cooperative Medical Science Program against Tuberculosis and Leprosy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-6-6645-3746; Fax: 81-6-6645-3747; E-mail: sohkichi{at}med.osaka-cu.ac.jp.

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