Toxoplasma, suicidal behaviour and the kynurenine pathway
Tryptophan, an essential amino acid, and its degradation pathway enzymes and metabolites are central to interactions between the microorganism and the host, in particular its immune cells involved in antimicrobial resistance. Certain commensal organisms capable of synthesising tryptophan (TRP) (autotrophs) provide supplementary TRP to complement dietary sources for their host organism. In contrast, many pathogenic microorganisms trigger the host’s indoleamine 2,3-dioxygenase enzymes (IDO) and subsequent catabolic pathway enzymes, resulting in TRP depletion and the production of active metabolites that collectively downgrade the immune system’s antimicrobial functions (Zhang and Rubin 2013). However, numerous intracellular pathogens, being TRP auxotrophs, depend completely on their host organisms for TRP acquisition.
This metabolic dependency makes these pathogens susceptible to the host’s defensive mechanism of depleting local TRP concentrations, thereby restricting pathogen proliferation and virulence (Ren et al. 2018, Costantini et al. 2020). Among mammalian parasites, several species exhibit TRP auxotrophy, with T. gondii being one of the most notable examples. Toxoplasma gondii triggers IDO-1 activation through pro-inflammatory cytokines, leading to TRP catabolism into KYN. While this serves to deprive T. gondii of essential TRP (Pfefferkorn 1984), it also in- creases KYN metabolites that cross the blood-brain bar- rier and modulate NMDA receptor function through compounds like quinolinic acid (QUIN) which is excitotoxic, and kynurenic acid (KYNA) which is neuroprotective.
Approximately fifteen years ago I initiated a collabo- ration with the suicidologist John Mann and his group at Columbia University. Our collaboration identified for the first time a link between suicidal behaviour in individuals with major depression and elevated blood level of KYN (Sublette et al. 2011). KYN is the immediate metabolite of TRP via the IDO-1 pathway a molecule with production upregulated by proinflammatory cytokines and stress (Sublette and Postolache 2012). I remember at that time the conversations with my Columbia collaborators who were focused on serotonin and suicide, and how TRP depletion would make sense. Yet, implicating KYN production be- yond TRP depletion, with NMDA agonism by QUIN and NMDA antagonism by KYNA simply appeared to them implausible. I remember the joy of seeing the first email of the Columbia statistician with the results showing that it was indeed the high KYN, and not low TRP, that was significantly associated with suicidal behaviour.
Following up on our first report on the positive asso- ciation between plasma KYN and suicidal behaviour in individuals with major depression (Sublette et al. 2011) collaborative work with Lena Brundin’s group has focused on neuroactive kynurenine metabolites in the cerebrospinal fluid (CSF) and later, both CSF and blood. The sam- pling occurred in hospitalised patients recently admitted for suicide attempt, with longitudinal follow up. It identified state-dependent associations between recent suicidal behaviour and high excitotoxic QUIN levels (Erhardt et al. 2013) and low neuroprotective picolinic acid PIC or KYNA levels (Brundin et al. 2015).
These results led us to evaluate associations with suicidal behaviour of interactions between T. gondii and plasma KYN in individuals with schizophrenia (Okusaga et al. 2016). We found that elevated plasma KYN was associated in a nonlinear fashion with history of suicidal behaviour only in seropositive individuals but not those seronegative for T. gondii. This cumulative nonlinear effect suggests several potential intertwined biological processes. Considering the immunosuppressive effect of certain kynurenines, it is possible that high KYN will result in a lower immune pressure on the bradyzoites which will reactivate more often and more intently, transforming into tachyzoites and invading other sites, organs and tissues. For this effect of the potential immunosuppressive effect of KYN to become manifest it is important to have a chronic latent infection with potential for reactivation, otherwise the KYN eleva- tion is unrealised.
Additionally, the results of this paper also suggested that inflammation (which activates IDO to shunt serotonin towards the KYN pathway) or KYN levels are not suffi- cient to be associated with suicidal behaviour in the entire sample of schizophrenia patients. Similarly, in the entire sample T. gondii seropositivity was not associated with suicidal behaviour, consistent with negative results of meta-analyses when selecting solely patients with schizophrenia (Sutterland et al. 2019). Our results suggest that despite schizophrenia, including its new onset, being a condition strongly associated with T. gondii (Mortensen et al. 2007, Torrey et al. 2007, 2012), suicidal behaviour in patients with schizophrenia is associated with T. gondii only in younger patients (Okusaga et al. 2011a), or in those with high KYN (Okusaga et al. 2016).
It may be possible that because of the consistent associations of schizophrenia and both T. gondii (Mortensen et al. 2007, Torrey et al. 2007, 2012) and alterations of ky- nurenine pathways (Wonodi and Schwarcz 2010, Plitman et al. 2017) – the individuals with schizophrenia who did not attempt suicide manifested elevations in serointensity and kynurenines sufficiently to blunt the links of T. gondii and kynurenine levels analysed individually.
Fifteen years ago, my hopes were high that we would be able to be effective by addressing T. gondii etiologically and engaging physiologically the KYN pathway to (fundamentally) prove causality and (clinically) reduce the risk for SSDV. But, alas! Here we are 15 years later, with not much progress, at least for now. In general, we have no effective intervention for chronic toxoplasmosis in immu- nocompetent hosts, more specifically for helping patients with schizophrenia and other mental illnesses who are positive for T. gondii with incomplete response to psychotropics, and we have no currently clinically immediately available pharmacological agents in use to directly target specifically the KYN pathway and chronic toxoplasmosis.
In my clinician scientist experience this is a relative disappointment by comparison to other environmental triggers, perpetuators and exacerbators. For other sources of chronic or reactivating inflammation we have proven in- terventions. For instance we have dental root scaling and planning, and antibiotics targeting anaerobes, for periodontal disease, intranasal corticosteroids for allergic and infectious acute or chronic rhinosinusitis, pre- and probiotic agents as well as butyrate interventions to reduce intestinal permeability for gastrointestinal pathogens. For herpes 1 and 2 and CMV and HIV we have antivirals to prevent and reduce reactivation and for Lyme disease specific anti- microbials and anti-inflammatories.
Publication Date: 2025-09-05