Induction of IDO by Bacille Calmette-Guérin Is Responsible for Development of Murine Depressive-Like Behavior

Abstract

Chronic inflammation activates the tryptophan-degrading enzyme IDO, which is well known to impair T cell proliferation. We have previously established that bacille Calmette-Guérin (BCG), an attenuated form of Mycobacterium bovis, is associated with persistent activation of IDO in the brain and chronic depressive-like behavior, but a causative role has not been established. In these experiments we used both pharmacologic and genetic approaches to test the hypothesis that IDO activation is responsible for the development of chronic depression that follows BCG infection. BCG induced TNF-α, IFN-γ, and IDO mRNA steady-state transcripts in the brain as well as the enzyme 3-hydroxyanthranilic acid oxygenase (3-HAO) that lies downstream of IDO and generates the neuroactive metabolite, quinolinic acid. Behaviors characteristic of depression were apparent 1 wk after BCG infection. Pretreatment with the competitive IDO inhibitor 1-methyltryptophan fully blocked BCG-induced depressive-like behaviors. Importantly, IDO-deficient mice were completely resistant to BCG-induced depressive-like behavior but responded normally to BCG induction of proinflammatory cytokines. These results are the first to prove that the BCG-induced persistent activation of IDO is accompanied by the induction of 3-hydroxyanthranilic acid oxygenase and that IDO is required as an initial step for the subsequent development of chronic depressive-like behavior.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Laboratory animal studies have provided a rich array of experiments that demonstrate the role of IDO and its activation of the kynurenine pathway (KP) in the development of depressive symptoms in the context of a variety of immune stimuli. Studies in mice exposed to LPS as well as Bacille CalmetteGuerin (BCG) have demonstrated that inhibition of IDO by 1 methyltryptophan (1 MT) completely reversed increases in the kynurenine/tryptophan ratio and reversed depressiveand anxiety-like behaviors including sucrose preference, whereas it had no effect on inflammatory markers in the brain (O'Connor et al, 2009;Salazar et al, 2012). Although much attention has been paid to the two primary pathways downstream of IDO leading to quinolinic acid (the 'neurotoxic pathway') and kynurenic acid (the 'neuroprotective pathway'), data suggest that this distinction may be too simplistic, and it is very apparent that both pathways can contribute to pathology.…”

Model of Tryptophan Metabolism, Readily Scalable Using Tissue-specific Gene Expression Data

“…Moreover, our simulations predict that the ratio of mean fluxes through KAT/KMO decreased by 28.1% in T. meningitis patients. O'Connor et al (41) showed that induction of IDO by Bacille Calmette-Guerin (a pathogen widely used as a vaccine against tuberculosis) is responsible for a depressive-like behavior in mice. They proposed that a shift to a less favorable ratio of neuroprotective and neurotoxic kynurenine derivatives could contribute to a depressive phenotype.…”

Risk of clinically significant depression in HIV‐infected patients: effect of antiretroviral drugs

“…Several investigations have focused on potential mechanisms linking inflammation-induced depression to tryptophan metabolism, as a reduction in the bioavailability of tryptophan could affect serotoninergic neurotransmission in the brain, leading to depressive symptoms [28,29]. Those studies have shown that the proinflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and lipopolysaccharide (LPS), are capable of activating the enzyme indoleamine 2, 3-dioxygenase (IDO) [30][31][32], a tryptophan-degrading enzyme that oxidizes tryptophan to n-formylkynurenine. A hallmark of HIV infection is the presence of abnormal levels of immune activation and inflammation with high concentrations of proinflammatory cytokines, and high plasma LPS levels [33].…”