Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase

Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide anal ogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymp hocyte immune responses. Based on these activities, we investigated whether ISS-ODN could modify the course of Mycobacterium avium infection. Al. aviu m growth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and Al. avium growth in vivo was similarly inhibite d in C57BL/6 mice treated with ISS-ODN. This protective effect of ISS-ODN w as largely independent of tumor necrosis factor alpha (TNF-alpha), interleu kin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-alp ha/beta), and IFN-gamma. In contrast, we found that the induction of indole amine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect o f ISS-ODN. To evaluate the potential for synergism between ISS-ODN and othe r antimycobacterial agents, treatment with a combination of ISS-ODN and cla rithromycin (CLA) was tested in vitro and in vivo. ISS-ODN significantly en hanced the therapeutic effect of CLA in both human and mouse macrophages an d 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 w hen used in combination with conventional chemotherapy for microbial infect ions.