title: Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: S P
authors.initials: SP
authors.lastname: Rao
authors.forename: K
authors.initials: K
authors.lastname: Takabayashi
authors.forename: J H
authors.initials: JH
authors.lastname: Van Uden
authors.forename: R S
authors.initials: RS
authors.lastname: Kornbluth
authors.forename: S M
authors.initials: SM
authors.lastname: Baird
authors.forename: M W
authors.initials: MW
authors.lastname: Taylor
authors.forename: D A
authors.initials: DA
authors.lastname: Carson
authors.forename: A
authors.initials: A
authors.lastname: Catanzaro
authors.forename: E
authors.initials: E
authors.lastname: Raz
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D017291:Clarithromycin / Q000494:pharmacology; D004247:DNA / Q000276:immunology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D009162:Mycobacterium avium / Q000254:growth & development / Q000276:immunology; D019255:NADPH Oxidases / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D013873:Thionucleotides / Q000276:immunology*; D014366:Tryptophan Oxygenase / Q000276:immunology*; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma; D004247:DNA; D014366:Tryptophan Oxygenase; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019255:NADPH Oxidases; D017291:Clarithromycin