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Infectious Disease and Neurocognition
is milder than those related to other environmental or genetic factors, then memory
of Toxoplasma- infected subjects could be better even if toxoplasmosis does have a
detrimental impact on cognitive performance, including memory functions; for further explanation of this phenomenon, see the “birth weight paradox” in Pearl and
Mackenzie (2018).
In the second decade of the twenty- rst century, there appeared several studies
performed on general populations. Some of these, however, reported the results of
independent analyses performed on the same population (based on the NHANES).
For example, a cross- sectional study performed on 4485 senior members of
NHANES III showed that Toxoplasma- infected subjects had worse immediate but
intact delayed memory compared to Toxoplasma- free survey participants (Mendy
et al., 2015). Similarly, a longitudinal 5- year study performed on a cohort of 1022
older participants of the Monongahela– Youghiogheny Healthy Aging Team study
examined annually using a panel of cognitive tests, including the memory tests,
showed that individuals infected with Toxoplasma but also herpesviruses (cyto-
megalovirus, herpes simplex virus (HSV)- 2, but not HSV- 1) showed a signicantly
greater cognitive decline over time than non- infected individuals did (Nimgaonkar
et al., 2016).
A recent systematic meta- analytical study (De Haan et al., 2021) identied 13 independent studies that reported a strong association between latent toxoplasmosis
and various cognitive functions, including working memory and verbal memory in
non- clinical populations. e authors found six studies reporting the eects of toxoplasmosis on working memory with aggregate standardized mean dierence = 0.16,
p = 0.002, and ve studies reporting short- term word memory with aggregate standardized mean dierence = 0.18, p < 0.001.
Proximal causes of Toxoplasmosis- associated
behavioral changes
e molecular and physiologic mechanisms underlying the behavioral changes remain unknown. Several molecules, including dopamine, tryptophan and its metabolites, and testosterone, have been named as possibly playing a role in inducing these
changes.
Dopamine is not only a neurotransmitter but also an important cytokine produced by some populations of leukocytes to enable an exchange of information
between immunocytes in the course of immune processes. It is known that latent
toxoplasmosis is associated with characteristic changes in the immune system in
both rodents and humans (Flegr & Stříž, 2011; Kaňková et al., 2010). In the brain of
infected mice, researchers found numerous perivascular and leptomeningeal inltrations of inammatory cells (Figure 14.2) (Berenreiterová et al., 2011) located in
dierent brain regions than the tissue cysts with bradyzoites (Berenreiterová et al.,
2011; Hermes et al., 2008). Moreover, the local immune response needed to keep
Toxoplasmosis, Behavior, and Cognition 219
Figure 14.2 Perivascular infiltrations of inflammatory cells in the brain of a mouse infected
with Toxoplasma gondii.
Source: Berenreiterová, M., Flegr, J., Kubena, A. A. & Nemec, P. 2011. The distribution of Toxoplasma gondii
cysts in the brain of a mouse with latent toxoplasmosis: Implications for the behavioral manipulation
hypothesis. PLoS One, 6, e28925.
Toxoplasma dormant may— through the production of proinammatory cytokines,
interferon gamma, and indoleamine 2,3- dioxygenase— alter the levels, turnover,
and eciency of many neuromodulators, including dopamine, glutamate, and serotonin (for details see, e.g., Skallová et al., 2005; Webster & McConkey, 2010). e
dopamine hypothesis of Toxoplasma manipulation, proposed in 2003, was based
on ndings regarding an increased concentration of dopamine in the brain of infected mice (Stibbs, 1985), on the well- known association between toxoplasmosis
and schizophrenia (which is associated with and possibly caused by an increased
concentration of dopamine in some regions of the brain of patients) (Carlsson, 1988;
Creese et al., 1976), and on the results of human studies showing a decreased level
of novelty seeking (a trait associated with high concentrations of dopamine in the
brain tissue) (Flegr et al., 2003; Skallová et al., 2005). e hypothesis later received
further support from the results of ethnopharmacological study performed on rodents (Skallová et al., 2006). e original dopamine hypothesis supposed that dopamine is produced by the host’s leukocytes, which are stimulated by the presence of
Toxoplasma in the brain tissue. A later bioinformatic study, however, found that the
genome of T. gondii contains two unique enzymes, which catalyze a limiting step of
dopamine synthesis (Gaskell et al., 2009). An immunohistological study moreover
demonstrated that the tissue cysts of Toxoplasma and their surrounding contain
high concentrations of this neurotransmitter (Prandovszky et al., 2011).
Infectious Disease and Neurocognition
Another molecule suspected of playing a role in the behavioral symptoms of latent toxoplasmosis is testosterone. It is known that male rats articially infected with
Toxoplasma (Lim et al., 2013; Tan & Vyas, 2016; Vyas, 2015), as well as men with
latent toxoplasmosis (Flegr et al., 2008a, 2008b), have increased levels of this sex
hormone in the serum. Some indirect evidence of increased levels of testosterone
in Toxoplasma- infected men has been reported in earlier studies. For example, in-
fected male students were rated as more masculine and dominant (Hodkova et al.,
2007) and were, on average, 3 cm taller than their Toxoplasma- free peers (Flegr et al.,
2005). It has been suggested that Toxoplasma induces testosterone synthesis in the
testes to inhibit the host’s immunity or to boost the sexual activity of infected males,
which in turn increases the likelihood of sexual transmission between intermediate
hosts (Flegr, 2015). On the other hand, the fact that Toxoplasma infection can induce
the fatal attraction phenomenon (a loss of fear response to cat odor and its switch to
attraction to that odor) in intact but not in castrated male rats (Lim et al., 2013) suggests that testosterone probably plays a far more specic role in the behavioral eects
of toxoplasmosis.
e third class of molecules suspected of playing a proximal role in the induction of
behavioral changes in Toxoplasma- infected hosts is tryptophan and its metabolites,
specically kynurenic acids. It has been suggested that an increased concentration
of this product of degradation of tryptophan could be responsible for an inhibition
of glutamine and nicotine neurotransmitter receptors, both of which probably play
an essential role in the symptoms of cognitive impairment associated with schizophrenia (Schwarcz & Hunter, 2007). A study performed on 950 non- clinical subjects
showed that metabolites of tryptophan probably mediate the eect of toxoplasmosis
on impulsivity in young men (Peng et al., 2018). While dopamine upregulation is
usually considered a part of Toxoplasma’s manipulation activity (Barnard & Behnke,
1990), tryptophan degradation is part of a vertebrate host’s defense against various
endoparasites, including Toxoplasma (MacKenzie et al., 2007).
It is, of course, possible that other molecules could also play a role in the behavioral
eects of toxoplasmosis. For example, a recent study based on data from NHANES
III showed that Toxoplasma could aect the concentration of folate and vitamin B12
in human brain and that these changes could be responsible for the decreased performance of infected individuals in specic performance tests (Berrett et al., 2017).
Manipulation or side eects of the disease?
For a long time, it had been thought that latent toxoplasmosis has no adverse eects
on the health of infected subjects. In the past three decades, however, we have witnessed the publication of numerous anecdotal clinical observations that challenge
this view (see the review part of Flegr et al., 2014). Within the past decade, several
large cohort studies performed on the general population, as well as one ecological
study, showed that latent toxoplasmosis does have a serious impact on physical and
Toxoplasmosis, Behavior, and Cognition 221
mental health. Toxoplasma- infected subjects suer from many diseases, including
those with a severe impact on public health (such as hypertensive heart disease), as
well as certain psychoses, signicantly more oen than Toxoplasma- free subjects.
Toxoplasma- infected individuals also scored worse on 28 of 29 health- related variables examined in the study (Flegr & Escudero, 2016; Flegr & Horáček, 2017, 2020;
Šebánková & Flegr, 2017). e prevalence and incidence of many diseases and disorders and their impact on public health (measured as disability- adjusted life years)
positively correlates with the prevalence of latent toxoplasmosis both worldwide
and in European countries specically (Flegr et al., 2014). When per capita gross
domestic product, latitude, and humidity were controlled for, dierences in the
prevalence of toxoplasmosis explained approximately 23 percent of variability in
the total disease burden in 27 European countries. ese new results suggest that
Toxoplasma- infected subjects are chronically ill, either due to toxoplasmosis or due
other disorders associated with a lifelong Toxoplasma infection. erefore, a pos-
sible and parsimonious explanation of the observed behavioral changes is that they
are the side eect of chronic or returning diseases rather than the eect of any manipulative activity of Toxoplasma.
is side eect hypothesis was recently tested in a study performed on a cohort
of 7762 members of the internet population using a 2- hour- long survey consisting
of a panel of questionnaires and performance tests (Flegr et al., 2023). e results
showed that subjects infected with Toxoplasma were in worse physical and mental
health than the corresponding controls. e infected and non- infected subjects also
diered in their behavioral and personality traits (conscientiousness, pathogen disgust, injury disgust, Machiavellianism, narcissism, tribalism, anti- authoritarianism,
intelligence, reaction time, and precision). Structural equation modeling and nonparametric partial Kendall correlation tests controlled for physical or mental health
showed that the observed behavioral eects were not mediated by impaired health
of the infected individuals (Figure 14.3). In general, these results contradict the predictions of the side eects hypothesis and support the hypothesis that behavioral
changes are in fact a direct eect of toxoplasmosis. Of course, these ndings cannot
falsify other (untested) hypotheses, for example, that the observed behavioral
changes are the product of manipulation activity of Toxoplasma aimed primarily at
an inhibition or modulation of activity of the immune system of Toxoplasma hosts.
Conclusion
Research on the behavioral eects of toxoplasmosis on rodents started approximately 50 years ago and 30 years ago expanded to studies on infected humans. Since
then, it has been found that latent Toxoplasma infection has a variety of both specic
and nonspecic eects on the behavior of intermediate hosts and their performance
in dierent cognitive performance tests. It is unclear whether the observed behavioral changes are the product of manipulation activity of the parasite, that is, whether
age
sex
0.14***
‒0.16***
conscientiousness
‒0.03
‒0.09**
‒0.09**
mental sickness
sex age
‒0.22***
0.07*
0.11***
0.08*
‒0.00
‒0.10***
‒0.08*
mental sickness
0.07*
sex age
‒0.07*‒0.08*
‒0.19***
0.03
‒0.02
‒0.06
mental sickness
age
sex
‒0.09**
0.15***
‒0.15***
0.12*** 0.12***
‒0.09**
toxoplasmosis
conscientiousness
‒0.10** ‒0.18***
0.06
‒0.10**
‒0.08*
0.06 0.05
toxoplasmosis
physical sickness
sex age
‒0.10***
‒0.22***
0.07*
0.11***
‒0.10***
toxoplasmosisintelligence intelligence
0.06
0.08*
‒0.07*
toxoplasmosis
‒0.08*
physical sickness
0.08*
sex age
‒0.08**
‒0.18***
0.12*** 0.12***
‒0.08**
pathogen disgust pathogen disgust
0.12**0.06 0.06
0.06
‒0.07*
‒0.08* ‒0.09**
toxoplasmosis toxoplasmosis
physical sickness
Figure 14.3 The results of path analyses showing that impaired health is not responsible for the eects of toxoplasmosis on human personality and cognitive
performance. Green arrows show positive, red arrows negative, and black arrows non- significant correlations. The numbers (standardized path coeicients)
and arrow widths indicate the strength of correlations. The number of asterisks (one, two, or three) indicates their significance (0.05, 0.01, and 0.001,
respectively).
Toxoplasmosis, Behavior, and Cognition 223
they are the result of an evolutionary adaptation of T. gondii. It is, however, clear
that many of these changes are the product of Toxoplasma infection and that the in-
tensity of some of these changes gradually increases with duration of the infection.
Moreover, some behavioral changes might have a severe practical impact on human
life and public health. For example, the increased risk of trac and workplace accidents might be responsible for hundreds of thousands of unnecessary deaths.
Similarly, the increased level of dopamine, which in most people probably leads
only to a decrease in novelty seeking, could in predisposed people lead to the development of schizophrenia or obsessive– compulsive disorder. Possibly the most
important result of the past 50 years of research on the behavioral eects of toxoplasmosis is the realization that this widespread form of the disease is not clinically asymptomatic: it has a varied and strong impact on the physical and mental
health of the general population. e main practical output of these studies is the
recognition that an oral vaccine for feral, stray, and pet cats is urgently needed to
either eradicate T. gondii or at least signicantly decrease its prevalence in popu-
lated areas.
Acknowledgments
I want to thank Anna Pilátová for the nal revisions of our text and the Czech Science
Foundation, grant number 22- 20785S for nancial support.
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