Our team's discovery of the link between chronic "latent" infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) and suicidal behaviour, and our subsequent cross-diagnostic confirmatory work and mechanistic extensions, evolved from our neuroimmunology studies on affective and behavioural dysregulation exacerbated by allergic sensitisation and allergen exposure. Another root was studying behavioural changes and cytokine gene expression in the brain of rodents sensitised and exposed to aeroallergens. We "piggy-backed" our project funded to study coupling between aeroallergen sensitisation and exposure in patients with recurrent mood disorders, by measuring Toxoplasma gondii (T. gondii) antibodies in existing samples, and found associations between IgG serointensity and past suicide attempts. Successively, we then reported significant associations between T. gondii seropositivity and/or serointensity and suicidal behaviour in patients with schizophrenia in Germany, recent attempters in Sweden, and longitudinally in a cohort of Danish mothers. In the Danish mothers the exposure to T. gondii preceded self-directed harm and violent suicide attempts; the association was stronger with higher serointensity strata demonstrating a dose-effect. Furthermore, we identified links between T. gondii IgG and suicide endophenotypes of aggression and impulsivity in both individuals with no history of mental illness, and in patients with Intermittent Explosive Disorder (IED). We also found associations between T. gondii and risk factors of suicidal behaviour such as hopelessness and anhedonia in the Amish, depressive symptoms in pregnant women and women Veterans, frailty in older adults, and cognitive deficits in patients with bipolar disorder. Recently, we reported positive associations between T. gondii IgG serointensity with suicidal ideation, impulsivity, depression scores, and daytime dysfunction due to sleep problems in US Veterans who previously attempted suicide. Toxoplasma gondii emerged rather unexpectedly and then took over a considerable proportion of our neuroimmune research portfolio. It satisfied both intellectual appetites, and brought celebrations of discovery, with three systematic reviews and meta-analyses published to date, and a substantial majority of primary articles confirming our initial observations. Toxoplasma gondii also brought considerable frustrations, such as initial grant application setbacks, inability to completely demonstrate causality and, so far, prophylactic and therapeutic impotence for mental health applications in general. While we do not have, as of today, effective and safe treatments for chronic toxoplasmosis with demonstrated mental health benefits in immunocompetent hosts, there are reasons to be optimistic regarding future discoveries. These may include vaccines, novel medications using in silico exploration with biological confirmation, trials of reactivation prevention, as well as identification and targeting of mediating mechanisms. Yet the most justified reasons for optimism are the potential to apply machine learning (ML) and artificial intelligence (AI) methodologies to big data with a focus on interaction and causal inference. These novel approaches, utilising ML-weighted models that emulate randomised trials in electronic medical records, have the potential to reveal not only if T. gondii elevates risk and to what extent, but also for whom specifically, under which demographic, clinical and physiological circumstances, and what factors, or combinations thereof, might mitigate this risk.

Mental Illness Research Education and Clinical Center 5 VA Capitol Health Care Network Baltimore MD USA

Mood and Anxiety Program Division of Biological Psychiatry Department of Psychiatry University of Maryland School of Medicine Baltimore MD USA

Veterans Health Administration Rocky Mountain Mental Illness Research Education and Clinical Center 19 Aurora CO USA *Address for correspondence Teodor T Postolache Mood and Anxiety Program Division of Biological Psychiatry Department of Psychiatry 685 West Baltimore Street MSTF Building Room 930 Baltimore MD 21201 USA E mail ORCID 0000 0001 6056 4244

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