Tryptophan-kynurenine pathway attenuates β-catenin-dependent pro-parasitic role of STING-TICAM2-IRF3-IDO1 signalosome in Toxoplasma gondii infection

Abstract

Recent studies have documented the diverse role of host immunity in infection by the protozoan parasite, Toxoplasma gondii. However, the contribution of the β-catenin pathway in this process has not been explored. Here, we show that AKT-mediated phosphorylated β-catenin supports T. gondii multiplication which is arrested in the deficiency of its phosphorylation domain at S552 position. The β-catenin-TCF4 protein complex binds to the promoter region of IRF3 gene and initiates its transcription, which was also abrogated in β-catenin knockout cells. TBK-independent phosphorylation of STING(S366) and its adaptor molecule TICAM2 by phospho-AKT(T308S473) augmented downstream IRF3-dependent IDO1 transcription, which was also dependent on β-catenin. But, proteasomal degradation of IDO1 by its tyrosine phosphorylation (at Y115 and Y253) favoured parasite replication. In absence of IDO1, tryptophan was catabolized into melatonin, which supressed cellular reactive oxygen species (ROS) and boosted parasite growth. Conversely, when tyrosine phosphorylation was abolished by phosphosite mutations, IDO1 escaped its ubiquitin-mediated proteasomal degradation system (UPS) and the stable IDO1 prevented parasite replication by kynurenine synthesis. We propose that T. gondii selectively utilizes tryptophan to produce the antioxidant, melatonin, thus prolonging the survival of infected cells through functional AKT and β-catenin activity for better parasite replication. Stable IDO1 in the presence of IFN-γ catabolized tryptophan into kynurenine, promoting cell death by suppressing phospho-AKT and phospho-β-catenin levels, and circumvented parasite replication. Treatment of infected cells with kynurenine or its analogue, teriflunomide suppressed kinase activity of AKT, and phosphorylation of β-catenin triggering caspase-3 dependent apoptosis of infected cells to inhibit parasite growth. Our results demonstrate that β-catenin regulate phosphorylated STING-TICAM2-IRF3-IDO1 signalosome for a cell-intrinsic pro-parasitic role. We propose that the downstream IRF3-IDO1-reliant tryptophan catabolites and their analogues can act as effective immunotherapeutic molecules to control T. gondii replication by impairing the AKT and β-catenin axis.

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

“…IDO, in particular, is associated with infection and induced by IFN type I/II production, prostaglandins as well as microbial components [35,36]. Because pathogens are either tryptophan autotrophs (fully depending on host tryptophan), such as T. gondii and the mouse chlamydia strain, or at least benefit from host tryptophan for their development or growth, the host immune response upregulates IDO, decreasing its availability to pathogens [37][38][39]. Additionally, the metabolites arising from tryptophan degradation have antimicrobial effects themselves, thereby aiding in host-defense [40].…”

Rickettsial pathogen uses arthropod tryptophan pathway metabolites to evade reactive oxygen species in tick cells

“…The metabolites in the kynurenine pathway have different anti-and pro-oxidant properties that are essential in the maintenance of cell homeostasis (Han, Beerntsen, & Li, 2007). Among the kynurenine pathway metabolites, xanthurenic acid (XA) was shown to act as an antioxidant in Aedes aegypti midgut during digestion of blood meal (Lima et al, 2012) and kynurenine was shown to prevent Toxoplasma gondii growth through induction of apoptosis (Majumdar et al, 2019). The 3-hydroxyl-Lkynurenine (3-HK), another tryptophan metabolite, is shown to stimulate ROS production (Amaral & Outeiro, 2013;Han et al, 2007).…”

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

“…Recently, the requirement of β-catenin in the cGAS/STING mediated activation of the IFN pathway was shown in a reporter assay [119]. This could likely happen through the binding of p-β-catenin Ser552 with IRF3 promoter in association with TCF4, as reported following STING activation in Toxoplasma gondii infection [120]. It is interesting to note, however, that viral interference inhibiting the functions of both GSK-3 and β-catenin has been observed with many DNA viruses-encoded proteins including the hepatitis B virus (HBV) X protein [121], the Epstein-Barr virus (EBV) LMP2A [122,123], the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (KSHV) [124], and the US3 protein from HSV-1 [119].…”