Abstract
Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide analogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymphocyte immune responses. Based on these activities, we investigated whether ISS-ODN could modify the course of Mycobacterium avium infection. M. avium growth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and M. avium growth in vivo was similarly inhibited in C57BL/6 mice treated with ISS-ODN. This protective effect of ISS-ODN was largely independent of tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-alpha/beta), and IFN-gamma. In contrast, we found that the induction of indoleamine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect of ISS-ODN. To evaluate the potential for synergism between ISS-ODN and other antimycobacterial agents, treatment with a combination of ISS-ODN and clarithromycin (CLA) was tested in vitro and in vivo. ISS-ODN significantly enhanced the therapeutic effect of CLA in both human and mouse macrophages and in C57BL/6 mice. This study newly identifies IDO as being involved in the antimicrobial activity of ISS-ODN and suggests the usefulness of ISS-ODN when used in combination with conventional chemotherapy for microbial infections.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic*
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Animals
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Anti-Bacterial Agents / therapeutic use
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Cells, Cultured
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Clarithromycin / pharmacology
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DNA / immunology
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DNA / therapeutic use
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Disease Models, Animal
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Interferon-alpha / immunology
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Interferon-beta / immunology
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Interferon-gamma / immunology
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Interleukin-12 / immunology
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Macrophages / cytology
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Macrophages / immunology
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Macrophages / microbiology
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Mice
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Mice, Knockout
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Monocytes / cytology
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Monocytes / immunology
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Monocytes / microbiology
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Mycobacterium avium / growth & development
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Mycobacterium avium / immunology
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NADPH Oxidases / immunology
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Nitric Oxide Synthase / immunology
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Nitric Oxide Synthase Type II
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Oligodeoxyribonucleotides / immunology*
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Oligodeoxyribonucleotides / therapeutic use
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T-Lymphocytes / immunology
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Thionucleotides / immunology*
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Tryptophan Oxygenase / immunology*
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Tuberculosis / drug therapy
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Tuberculosis / immunology*
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Tuberculosis / microbiology
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Tumor Necrosis Factor-alpha / immunology
Substances
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Adjuvants, Immunologic
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Anti-Bacterial Agents
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Interferon-alpha
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Oligodeoxyribonucleotides
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Thionucleotides
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Interferon-beta
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Interferon-gamma
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DNA
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Tryptophan Oxygenase
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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NADPH Oxidases
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Clarithromycin