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Reply to Brune M and Theiss C: Remaining questions in the relationship between T. gondii infection and major mental illness

Molecular Psychiatry volume 25, pages 4–5 (2020)Cite this article

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Brune and Theiss provided an evolutionary insight into our recent findings about the potential link between anti-T. gondii immunity and nonneuronal function of Disrupted In Schizophrenia 1 (DISC1) [1, 2]. Specifically, they propose that T. gondii may manipulate human behaviors by targeting the cells enriched in DISC1 expression, particularly von Economo neurons (VENs) in the anterior cingulate (ACC) and the anterior insula. VENs are atypical projection neurons known for their unique spindle shapes and have been identified more in humans than in nonhuman primates [3]. Altered number of VENs have been described in the behavioral variant of frontotemporal dementia (bvFTD), autism, and suicidal psychosis [4,5,6]. An earlier study also reported that DISC1 protein was preferentially expressed in these neurons in histology experiments [7]. Thus, Brune and Theiss hypothesized that the impact of T. gondii infection might be more profound in DISC1-enriched VENs than other cells [1]. Although this intriguing hypothesis needs further investigation, we generally agree with the authors on their concept that genetic variations in the cells more numerous and/or developed in humans, such as DISC1 variation in VENs, may play a critical role in the human-T. gondii interaction. Here we discuss additional remaining questions to be addressed in order to understand the biological mechanisms underlying the effects of T. gondii infection on the brain.

First, why does T. gondii infection lead to mental illness in some cases but not others? T. gondii seropositivity is highly associated with schizophrenia, but the seropositivity rate ranges between 10 and 60% across the human population and is usually higher than the frequency of schizophrenia [8]. Thus, not all patients with schizophrenia are seropositive for T. gondii. Accordingly, even if T. gondii infection participates in a causal process for schizophrenia, it only happens in a subpopulation of those infected and explains the causality only in a subpopulation of patients with schizophrenia. Thus, only individuals with genetic variations in the proteins critical for anti-T. gondii immune responses may lead to T. gondii-related brain dysfunction. In this regard, variations in nonneuronal proteins such as immune molecules could play key roles. With the recent discoveries of how genetic variations in immune pathways impact mental illness [9], there is now ample opportunity to explore the relationship between these genetic variations and T. gondii seropositivity. A larger cohort with blood samples will be central to the success of such a study. Indeed, a very recent study using a Danish cohort showed a promising result in exploring the relationship between pathogenic infections and major mental illness [10]. Further studies using these larger cohorts would identify various genetic variations associated with infections of pathogenic agents such as T. gondii. In addition, heterogeneity in T. gondii themselves should also be considered because different strains of T. gondii exhibit different virulence in infected animals [11].

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA

    Shin-ichi Kano

  2. Departments of Psychiatry, Neuroscience, Biomedical Engineering, and Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21287, USA

    Akira Sawa

  3. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21287, USA

    Akira Sawa

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  1. Shin-ichi Kano
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Correspondence to Shin-ichi Kano or Akira Sawa.

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Kano, Si., Sawa, A. Reply to Brune M and Theiss C: Remaining questions in the relationship between T. gondii infection and major mental illness. Mol Psychiatry 25, 4–5 (2020). https://doi.org/10.1038/s41380-019-0556-4

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