New Insights into IDO Biology in Bacterial and Viral Infections

Abstract

Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.

Keywords: IDO; bacterial infection; depressive disorders; kyn metabolites; viral infection.

Figure 1

Schematic summary of immunosuppressive functions of indoleamine-2,3-dioxygenase (IDO) during HIV infection. Direct induction of IDO in antigen-presenting cells (APC) by viral Tat protein is established via an intracellular signaling cascade including kinases (JakI, PI3K) or CTLA-4-B7 interaction on regulatory T (Treg)-cells with B7 co-receptor on the APC, which leads in consequence to a breakdown of tryptophan (Trp) into kynurenine (Kyn). Diminished anti-viral immune responses during chronic HIV infection is caused by an impaired T-cell response, the lack of potent IFNγ secreting DC, and the induction of immunosuppressive IDO⁺ APC. pDC, plasmacytoid DC; mDC, myeloid DC.

Figure 2

IDO links chronic viral and bacterial infections to cases of depression. Underlying mechanisms of the connection between chronic infection with viruses or bacteria and the onset of mental disorders in men are unknown. Insufficient levels of serotonin in chronically infected and depressive patients are thought to be the consequence of constitutively elevated levels of IDO. Murine models of chronic infections are established to decipher the involvement of IDO in the development of depressive-like behavior.

Figure 3

Schematic overview of the central role of IDO in immune responses to bacterial infections. Activation of IDO activity in bacteria-infected cells induces a potent bactericidal growth restrain to fight against spreading of the infection. Besides the induction of reactive oxygen species (ROS) and nitric oxide radicals, activity of IDO aids in Trp degradation to starve Trp auxotroph bacteria. A further species-specific bactericidal effect of increased IDO activation is the production of toxic Kyn metabolites. Recruitment of Treg cells and increasing levels of free ions might help as negative feedback loop to terminate inflammatory responses.