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Infection and Immunity, October 2001, p. 6156-6164, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6156-6164.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Enhancement of Innate Immunity against Mycobacterium avium Infection by Immunostimulatory DNA Is Mediated by Indoleamine 2,3-Dioxygenase

Tomoko Hayashi,1 Savita P. Rao,1 Kenji Takabayashi,1 John H. Van Uden,1 Richard S. Kornbluth,1 Stephen M. Baird,2 Milton W. Taylor,3 Dennis A. Carson,1 Antonino Catanzaro,1 and Eyal Raz1,*

Department of Medicine1 and Department of Pathology,2 University of California, San Diego, La Jolla, California 92093, and Department of Biology, Indiana University, Bloomington, Indiana 474053

Received 26 March 2001/Returned for modification 22 May 2001/Accepted 9 July 2001

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.

* Corresponding author. Mailing address: University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0663. Phone: (858) 534-5444. Fax: (858) 534-5399. E-mail: eraz{at}ucsd.edu.

Infection and Immunity, October 2001, p. 6156-6164, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6156-6164.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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