Toxoplasma gondii
The parasitic infection toxoplasmosis, which stems from the protozoan T. gondii, first isolated in a common gundi in Tunis in 1908 (Nicolle 1908), represents a major global health concern. Studies indicate that between 8 to 22 percent of the American population carries the infection (Jones et al. 2001, 2003, 2007, Dubey and Jones 2008) with higher rates in rural and farming communities, such as the Old Order Amish (Markon et al. 2020). Between 25 to 33 percent of the world population is infected (Pappas et al. 2009). It appears that environmental factors play a dominant role as compared to heritability, as my colleagues and I have reported in the Old Order Amish (Duffy et al. 2019). Toxoplasma gondii substantially affects mortality, morbid- ity and quality of life in humans, and also the health of domestic animals, wildlife and ecosystems.
Toxoplasma gondii sexually reproduces in the gut of felids, the definitive hosts, which excrete massive numbers of oocysts in their faeces (Frenkel et al. 1975). After spor- ulation, these oocysts are highly resistant to environmental hardship, thus leading to long-term infestation of the environment. After sporulation, oocysts contain infectious sporozoites that are remarkably potent: a single sporulated oocyst is sufficient to cause infection in intermediate hosts (any warm-blooded animal). Once crossing the intestinal barrier of an intermediate host, T. gondii spreads and reproduces asexually in the host’s tissues, slowly, including in the brain and the muscle (Miller et al. 1972, Dubey 2016).
My scientific trajectory towards T. gondii emerged from my prior engagement in the domain linking inflam- mation and suicidal behaviour (Erhardt et al. 2013, Brundin et al. 2015, Keaton et al. 2019, Neupane et al. 2023). For example, meta-analyses have confirmed associations between C-reactive protein (CRP) – an inflammation marker commonly used in clinical practice – and both suicidal ideation and behaviour (Miola et al. 2021). My research group was considered among the pioneers in establishing connections between inflammatory processes, their upstream triggers and perpetuators, and suicidal behaviour. Before we began exploring the Toxoplasma field, we had demonstrated that it is actually the specificity of coupling between allergic sensitisation and exposure that leads to depressive symptoms in individuals with bipolar disorder exposed to seasonal peaks of aeroallergens, even after adjustment for allergy symptom score (Manalai et al. 2012).
Our team was the first to describe the temporal associa- tion of the spring peaks of suicide (Postolache et al. 2010) with peaks of aeroallergens (Postolache et al. 2005, Qin et al. 2013) and had already published the first post-mortem study examining cytokine gene expression in the prefrontal cortex of suicide decedents. Notably, we discovered elevated levels of allergy-linked Type 2 cytokines in brain regions previously implicated in SSDV, specifically IL- 4 in women and IL- 13 in men (Tonelli et al. 2008). This led to our rodent studies that confirmed brain cytokine gene expression and behavioural alteration with intranasal administration of allergens (Tonelli et al. 2009) in previously sensitised and unsensitised animals.
The type 2 cytokines (previously called anti-inflam- matory or Th2 cytokines) initially received less attention in human behavioural dysregulation studies compared to their type 1 counterparts. However, more recent research has revealed their similarly important role in brain structure and function as key regulators of social behaviour, learning, memory (Zipp et al. 2023) and neurodevelopment (Barron et al. 2024). At that time, what grabbed my attention was that they are produced in response to allergens and parasites.
My literature search for parasites that infect the brain and are as widespread as aeroallergen sensitisation brought me to T. gondii. The results of the early projects on host manipulation by T. gondii were already published and they completely blew my mind (summarised by Vyas 2024 and Webster et al. 2025, in the same issue of the Folia Parasito- logica). I was further drawn to the published reports on associations between T. gondii and schizophrenia, reviewed by Fuller Torrey (Torrey 2024) and personality traits re- viewed by Jaroslav Flegr (Flegr 2025) in the same issue of Folia Parasitologica. Soon, my hypothesis of T. gondii being associated with suicidal behaviour was formed. Moreover, the samples on which we tested the aeroallergen sensitisation and exposure in patients with mood disorders in relationship to depression and history of suicide attempt were available for T. gondii serological analysis.
This led to the very first report of a link between T. gondii (in that first article – IgG serointensity) and suicidal behaviour in individuals with mood disorders (Arling et al. 2009). Prior to that article publication, if one would try to search for T. gondii AND (suicide OR suicidal) would get positive hits, but those publications invariably would prove not to be about suicidal behaviour in humans, but about suicidal behaviour in cells – i.e., apoptosis. Incidentally (with potential relevance for understanding identifying and targeting mechanisms), T. gondii induces apoptosis in certain cells and modulates it in others (Lüder and Gross 2005, Ahmadpour et al. 2023, Su et al. 2023).
The first author of our initial study, Tim Arling, current- ly a primary care physician in Washington, D.C., was at that time a medical student on an elective research rotation with my group. It was highly unusual at that time for a medical student to be able to coauthor an article in such a brief time as Tim did, and so much more first-author an article. Still, Tim had an outstanding intelligence, both factual and intuitive, dedication, and was an excellent writer. Moreover, “stars” were aligned favourably – with clinical data already in Excel spreadsheets with sufficient remain- ing samples. Critical intellectual support was received from Robert Sapolsky from Stanford University, and important logistical help was offered by Bob Yolken, who analysed our initial samples at no cost at the Stanley Division of Developmental Neurovirology at Johns Hopkins.
Our December 2009 publication (Arling et al. 2009) opened a new line of inquiry by establishing the first re- ported connection between T. gondii IgG serointensity and suicidal behaviour. We were really proud to be the very first who found this association. We always wrote “To our knowledge…we were the first), until at some point we dropped that and used instead “We were the first to re- port…” The significance of this finding was soon under- scored by two subsequent studies in 2010: Yagmur et al.’s emergency department study (Yagmur et al. 2010) com- paring T. gondii IgG seropositivity in suicide attempters versus healthcare workers and visitors (published in June 2010), and Lester’s ecological analysis (Lester 2010) correlating national suicide rates with T. gondii seropositivity in pregnant women (published in October 2010). Since then, many positive and several negative studies have been published, with four systematic reviews and three meta-analyses confirming a significant positive association between T. gondii IgG seropositivity and serointensity with SSDV, with no systematic review or meta-analysis reaching a different conclusion (Sutterland et al. 2019, Amouei et al. 2020, Soleymani et al. 2020, Zerekidze et al. 2024).
Following our initial uncovering of the association in mood disorders (Arling et al. 2009), we pursued a systematic investigation of T. gondii ’s relationship with suicidal behaviour across diagnostic boundaries. This approach was founded on the understanding that suicide risk factors and mechanisms only partially overlap with the presence or severity of often-implicated mental conditions (Xu et al. 2023). We first conducted a study of suicidal behaviour in 1000 patients with schizophrenia. In younger patients with schizophrenia, we found a significant association between T. gondii seropositivity and history of non-lethal suicide attempt (OR 1.59, 95% CI 1.06–2.40, p = 0.03). Notably, we found no significant associations between suicidal be- haviour and the other chronic pathogens cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1), or with certain immune triggers (gliadin), thereby suggesting at that time a potential specific role of chronic infection with T. gondii (Okusaga et al. 2011a).
One of the limitations of our initial studies, as in most studies that emerged at that time, was that the attempt preceded the blood collection for the serology of T. gondii, and the interval of time between the attempt and T. gondii IgG determination was highly variable, and often unknown. To address this issue, I initiated two collaborations in Scandinavian countries, one clinical in Lund, Sweden, and one epidemiological investigation nested in the Danish Registers. The first study was a collaboration with Lena Brundin, currently leading a very active clinical neuroimmunology research program in Grand Rapids, Michigan. Our first collaboration involved linking T. gondii serology with history of recent suicide attempt among individuals hospitalised for suicide attempts compared to healthy controls in Sweden, and with scores on a suicide rating scale employed in Sweden estimating risk of suicide in suicide attempters (Niméus et al. 2000).
The results were more robust than in previous studies on retrospective suicide attempts. IgG seropositivity and serointensity were significantly higher in suicide attempt- ers versus healthy controls; seropositivity was strongly associated with the scores on the Suicide Assessment Scale (SUAS), at that time, a promising scale in Sweden believed to be able to predict future suicide attempts (Zhang et al. 2012). The importance of the article consisted of the actual shortening of the time interval between the blood draw and prior attempt, the attempt’s recency, and clinically estimat- ed risk of suicide leading to a psychiatric inpatient admission in all cases. The limitations were the cross-sectional design and the use of healthy controls, but not including psychiatric controls.
Publication Date: 2025-09-05