Neuroscience and Biobehavioral Reviews 96 (2019) 72–92

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

Toxoplasmosis: A pathway to neuropsychiatric disorders T

a,b,c,⁎ a,b c,d a,b
Shiraz Tyebji , Simona Seizova , Anthony J. Hannan , Christopher J. Tonkin
a
The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
b
Department of Medical Biology, The University of Melbourne, Melbourne, 3052, Australia
c
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3052, Victoria, Australia
d
Department of Anatomy and Neuroscience, University of Melbourne, Parkville, 3052, Victoria, Australia

A R T I C LE I N FO A B S T R A C T

Keywords: Toxoplasma gondii is an obligate intracellular parasite that resides, in a latent form, in the human central nervous
Toxoplasma gondii system. Infection with Toxoplasma drastically alters the behaviour of rodents and is associated with the incidence
Neuroimmune of specific neuropsychiatric conditions in humans. But the question remains: how does this pervasive human
Neuropathology pathogen alter behaviour of the mammalian host? This fundamental question is receiving increasing attention as
Transgenerational
it has far reaching public health implications for a parasite that is very common in human populations. Our
Behavioural manipulations
Central nervous system
current understanding centres on neuronal changes that are elicited directly by this intracellular parasite versus
Inflammation indirect changes that occur due to activation of the immune system within the CNS, or a combination of both. In
this review, we explore the interactions between Toxoplasma and its host, the proposed mechanisms and con-
sequences on neuronal function and mental health, and discuss Toxoplasma infection as a public health issue.

1. Introduction tendency to develop mental health issues in life, such as malnutrition,

When the genetic architecture of complex human diseases was un-
covered by the genome-wide association studies, scientists quickly
realized that the expected Mendelian mechanism of inheritance cannot
be applied to many of the complex human traits and disorders observed
in the population (Maher, 2008; Manolio et al., 2009). This was re-
ferred to as the ‘missing heritability’, which may involve a wide range
of genetic, environmental and epigenetic factors (Eichler et al., 2010;
Hannan, 2010; Yeshurun and Hannan, 2018). In addition to rapid
progress in human genetics, various diseases, including mental health
disorders, are increasingly being associated with specific environmental
exposures and perturbations surrounding an individual. Researchers
have now identified numerous factors that could impact a person’s
exposure to heavy metals, urban living, socio-economic situation,
stress, drug abuse etc. (Uher and Zwicker, 2017). Apart from external
factors, the effect of gut flora on brain function has also revealed a bi-
directional gut-brain cross-talk that affects a person’s mood, motiva-
tion, cognitive abilities as well as decision making. Perhaps the most
intriguing and poorly understood link in the aetiology of mental health
is the effect of infections on brain function.
In 1979, it was discovered that infection of rodents with a ubiqui-
tous human parasite, Toxoplasma gondii, had drastic effects on learning
performance. Toxoplasma gondii is an obligate intracellular eukaryotic
parasite of the phylum Apicomplexa. Worldwide, 30%–80% of the
human population is known to carry the infection, which is acquired via
the consumption of contaminated water and food, or via vertical

Abbreviations: AAH, aromatic amino acid hydrolase; AD, Alzheimer’s disease; ADHD, attention deficit hyperactivity disorder; AMPA, α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid; APP, amyloid precursor protein; Aß, beta-amyloid; BBB, blood brain barrier; BD, bipolar disorder; BLA, basolateral amygdala; CNS, central
nervous system; CORT, corticosterone; DC, dendritic cells; DG, dense granules; EAE, autoimmune encephalomyelitis; EEG, electroencephalography; EM, electron
microscopy; GABA, gamma-aminobutyric acid; GAD67, glutamic acid decarboxylase 67; GAS, interferon gamma activated sequence; GLT-1, glutamate transporter-1;
HD, Huntington’s disease; HPA, hypothalamic-pituitary-adrenal; IDO, indoleamine 2,3-dioxygenase; IFNγ, interferon-gamma; IST, inhibitor of STAT1 transcriptional
activity; KA, kynurenic acid; KO, knock-out; MAP2, microtubule associated protein-2; MAPK, mitogen-activated protein kinase; MD, major depression; mGluR,
metabotropic glutamate receptor; miR-132, microRNA-132; MRI, magnetic resonance imaging; MS, multiple sclerosis; NK, natural killer cells; NMDA, N-methyl-d-
aspartic acid; NMDARs, NMDA receptors; NO, nitric oxide; NOS, nitric oxide synthase; PD, Parkinson’s disease; PSD-95, post-synaptic density protein-95; PSEN,
presenilin protein -1; PV, parasitophorous vacuole; PVM, parasitophorous vacuole membrane; QA, quinolinic acid; STAT1, signal transducer and activator of
transcription 1; SZ, schizophrenia; TBI, traumatic brain injury; TE, toxoplasma encephalitis; TH, tyrosine hydroxylase; VGLUT1, vesicular glutamate transporter 1;
WT, wild-type
⁎
Corresponding author at: The Walter and Eliza Hall Institute of Medical Research, 1G, Royal Parade, Parkville, Melbourne, 3052, Australia.
E-mail addresses: tyebji.s@wehi.edu.au (S. Tyebji), seizova.s@wehi.edu.au (S. Seizova), anthony.hannan@florey.edu.au (A.J. Hannan),
tonkin@wehi.edu.au (C.J. Tonkin).

https://doi.org/10.1016/j.neubiorev.2018.11.012
Received 25 May 2018; Received in revised form 23 October 2018; Accepted 22 November 2018
Available online 23 November 2018
0149-7634/ © 2018 Elsevier Ltd. All rights reserved.
S. Tyebji et al.
transmission during pregnancy (Montoya and Liesenfeld, 2004; Tenter
et al., 2000). Acute infection spreads throughout the body and presents
as mild flu-like symptoms, which is largely controlled by a healthy
immune system. Upon infection, acute-stage tachyzoites differentiates
into latent bradyzoite forms which reside in the muscle and CNS, and
are resistant to immune clearance thus leading to life-long chronic in-
fection. Whilst initially thought to be clinically silent, latent Toxoplasma
is now known to cause changes in learning and memory, locomotion,
anxiety, depression-like behaviours and novelty preference in rodents
(Table 1; Worth et al., 2014). However, the most fascinating effect of
Toxoplasma on rodent behaviour is its ability to cause rodents to lose
their natural aversion to cat odours (Berdoy et al., 2000; Vyas et al.,
2007). This is especially interesting as Toxoplasma is transmitted by
cats, thus suggesting that this cunning intracellular parasite may ma-
nipulate its host for transmission to its definitive host. How Toxoplasma
achieves this in a way that it undergoes minimal damage, avoiding
lethal outcome, is the focus of current research.
It has now been shown that Toxoplasma infection is associated with
several neuropsychiatric conditions thus posing interesting questions
regarding how the biology of the parasite and its interactions with the
brain and immune system could contribute to mental health disorders.
The mere association of seropositivity to Toxoplasma with the devel-
opment of mental disorders in humans does not answer critical ques-
tions such as: is Toxoplasma the cause of neurological and psychiatric
problems? Does Toxoplasma exacerbate the disease onset/symptoms in
susceptible individuals? What role does the parasite itself play in causing
these symptoms?
To date, studies evaluating the direct effects of Toxoplasma on
neurons and their associated neural functions have provided little
concrete evidence of cellular mechanisms that go awry in the presence
of this parasite, and even less that prove it is a direct result of parasitic
activity. In an attempt to understand the effects of Toxoplasma on host
behaviour, murine models of Toxoplasmosis have been developed
which have provided us with a good snapshot of the plethora of cog-
nitive changes caused as a result of infection (Worth et al., 2014). Apart
from changes in behaviour, a wide range of deficits have been observed
in the brain at the structural and functional level (Parlog et al., 2015;
Tedford and Mcconkey, 2017). Moreover, recent advancements in un-
derstanding the effects of immune activation on brain function have
indicated that direct parasite invasion of the brain as well as recruit-
ment of effector molecules from the peripheral immune system in re-
sponse to the CNS inflammation can lead to chronic neurological dys-
function that can persist long after pathogen clearance (Fung et al.,
2017; Klein et al., 2017; Yarovinsky, 2014). This opens up an intriguing
possibility that neurological changes observed upon infection could be
due to the host CNS altering itself as a defence mechanism against this
infection. Interestingly, above studies indicate no single definitive cause
for mental health disorders, genetic or otherwise, suggesting that a
combination of external and genetic factors could contribute to such
outcomes.
Although humans are secondary, dead-end hosts of Toxoplasma, its
effects on human neuropathology are still noteworthy. This review will
further propound the idea that the major threat from Toxoplasma to
apparently healthy but susceptible individuals is its role as an en-
vironmental modifier of disease onset and/or progression. Further, its
ability to affect the offspring of infected individuals, and its prevalence
in our society, begets an overhaul of our understanding of
Toxoplasmosis as a major public health issue. The indirect and un-
detected implications might outweigh the presence of the actual para-
site in its host. Here, we review our current understanding of changes in
brain functions upon infection, and link that to the changes observed in
known neuropsychiatric disorders.
2. Toxoplasma gondii – the organism
Toxoplasma is a single-celled obligate intracellular parasite,
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Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
meaning that it must invade host cells to replicate. Members of the
Felidae family are definitive hosts for Toxoplasma, wherein it undergoes
the sexual stage of its lifecycle within the gut. Fecal shedding leads to
environmental contamination of water and food sources, causing acute
infection in warm-blooded animals, including humans, when consumed
(Dubey, 2009). During the acute stage, tachyzoites, the fast-replicating
form of the parasite, go through cycles of invasion, replication and
egress, destroying the host cells in the process. Throughout its lifecycle,
the parasite secrets multiple parasite proteins into the host cells that
ensure its survival within the host (see Section 9). These secreted pro-
teins protect immune killing of Toxoplasma and allow it to persist and
hijack monocytes causing them to become hypermigratory, enabling
dissemination from the site of infection (the gut) and spread throughout
the body (Hammoudi et al., 2015; Kanatani et al., 2017; Lambert et al.,
2006; Weidner et al., 2016, 2013; Weidner and Barragan, 2014). Tox-
oplasma then undergoes differentiation into a slow growing encysted
form (bradyzoites) within cells of the muscle and CNS tissue (Dubey,
2008).
An area of active research is understanding how Toxoplasma is able
to cross blood-brain barrier (BBB). Three models have been proposed:
paracellular entry, transcellular migration, and infiltration of infected
immune cells (Fig. 1). The ability of Toxoplasma to cross the gut epi-
thelia via a paracellular pathway suggests that a similar means may be
applied to cross comparable barriers, such as the BBB (Barragan and
Sibley, 2002; Harker et al., 2014). Alternatively, it was demonstrated
that tachyzoites are able to invade and replicate inside the endothelial
cells of the BBB, finally bursting the cells and crossing over into the
brain parenchyma (Konradt et al., 2016). Lastly, a ‘Trojan horse’ me-
chanism has also been suggested; wherein acutely infected monocytes
cross the BBB, delivering the parasites into the brain parenchyma
(Lachenmaier et al., 2011; Lambert et al., 2006; Ueno et al., 2014). In
reality, it’s likely that a combination of these strategies is used by the
parasite to gain entry into the CNS (Fig. 1).
2.1. Tropism in the CNS
In the CNS, Toxoplasma has a selective tropism for neuronal cells
over resident glial cells and establishes a latent chronic infection by
differentiating into encysted bradyzoites (Fig. 1). Early in vitro experi-
ments used primary cells from murine and human foetal brains to study
the growth of Toxoplasma in astrocytes, microglia, and neurons
(Contreras-Ochoa et al., 2013; Fischer et al., 1997; Halonen et al., 2001,
1998, 1996; Jones et al., 1986; Lüder et al., 1999; Peterson et al., 1995,
1993). When a mixed culture of rat primary cortical cells were infected
with Toxoplasma, intracellular parasites were observed in all cell types;
but as infection progressed, astrocytes and microglia were able to ef-
ficiently inhibit the growth and replication of the parasites. Subse-
quently, vacuoles containing bradyzoites were observed predominantly
in neurons (Lüder et al., 1999). In studies with co-cultures of only
microglia and astrocytes, microglial cells could efficiently eliminate
parasites while cysts could be observed in astrocytes (Jones et al., 1986;
Peterson et al., 1993; Schlüter et al., 2001). Microglial cells were able to
clear parasites due to their intrinsic phagocytosis-associated anti-Tox-
oplasma activity (Jones et al., 1986; Peterson et al., 1993), possibly via
nitric-oxide (NO) mediated mechanisms (Chao et al., 1993; Gazzinelli
et al., 1993); while NO production (Peterson et al., 1995) and interferon
gamma (IFNγ) signalling (Fischer et al., 1997; Halonen et al., 2001;
Halonen and Weiss, 2000; Jones et al., 1986; Peterson et al., 1993;
Schlüter et al., 2001) inhibits intracellular parasite replication. The
development of cysts in astrocytes was not dependent on the presence
of IFNγ, but IFNγ did control the reactivation of tachyzoites that en-
abled cysts to remain for prolonged periods without rupturing (Jones
et al., 1986). It was recently demonstrated that the ability of IFNγ to
limit parasite replication was dependent on signal transducer and ac-
tivator of transcription 1 (STAT1) signalling in astrocytes, and deletion
of STAT1 in astrocytes led to an uncontrolled parasite replication
S. Tyebji et al. Neuroscience and Biobehavioral Reviews 96 (2019) 72–92

Fig. 1. Toxoplasma invasion of the brain. To successfully infect the brain and form cysts therein, the first challenge faced by Toxoplasma is to cross the BBB. It could do
so by one or more of the three proposed mechanisms: 1. Invade the epithelial cells of the blood vessel, replicate within and burst out into the brain parenchyma
(transcellular entry); 2. Hijack an immune cell and ride it across the BBB; 3. Adapt a paracellular mode of entry. After entry into the brain, the presence of Toxoplasma
leads to activation of microglia and astrocytes, leading to a heavy immune response that aids parasite clearance (A and B). Such events are thought to be responsible
for the lack of cysts observed in these cell types in vivo. On the other hand, the process of invasion of neurons by Toxoplasma is known to create three neuronal
subpopulations: C, cells that have been injected by rhoptry proteins, but remain uninfected; D, cells that harbor Toxoplasma in their tachyzoite forms; and, E, cells
that harbor stable parasite cysts. It is known that in their tachyzoite stages, Toxoplasma export DG proteins (GRA) across the parasitophorous vacuole membrane into
the host cell, but it’s ability to do the same in the stable cysts stage still remains a mystery. Elucidating if such protein export events occur in the chronic stages of
infection would help us understand mechanisms that lead to changes in neuronal function and behavioural alterations.

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Table 1
A summary of the documented behavioural changes upon infection with Toxoplasma gondii using rodent models. M, male; F, female; n/a, information not available.
Behavioural paradigm Effect Model Sex Toxoplasma strain Reference

Anxiety
Elevated plus maze Reduced Mouse F ME49 (Machado et al., 2016)
No change Rat M Pru (Vyas et al., 2007)
Reduced Rat n/a RH (Gonzalez et al., 2007)
Reduced Mouse F Pru & ME49 (Kannan et al., 2010)
Open field Reduced Mouse F ME49 (Afonso et al., 2012)
Increased Mouse M ME49 (Gatkowska et al., 2012)
Reduced Mouse M HIF (Skallová et al., 2006)
Increased Mouse F HIF (Skallová et al., 2006)
Increased Mouse n/a Rabbit A (Hay et al., 1984)
Recognition memory
Object recognition Reduced Mouse F ME49 (Machado et al., 2016)
Reduced Mouse F GT1 (Xiao et al., 2016b)
No change Mouse M ME49 (Gulinello et al., 2010)
Working Memory
Y-maze, No change Mouse F GT1 (Xiao et al., 2016b)
continuous alternations
No change Mouse n/a ME49 (Jung et al., 2012)
No change Mouse F Pru (Kannan et al., 2010)
Impaired Mouse F ME49 (Kannan et al., 2010)
Spatial Memory
Y-maze, No change Mice F GT1 (Xiao et al., 2016b)
time in novel arm
No change Mouse F Pru (Kannan et al., 2010)
No change Mouse F ME49 (Kannan et al., 2010)
Impaired Mouse n/a Rabbit A (Hay et al., 1984)
Impaired Mouse M N/a (Hutchison et al., 1980)
Morris water maze test No change Mouse n/a ME49 (Jung et al., 2012)
Impaired Rat M PTg(II) (Daniels et al., 2014)
No change Rat M Pru (Vyas et al., 2007)
8-arm radial maze Impaired Mouse F HIF (Hodkova et al., 2007)
Social food transmission No change Mouse F Pru (Xiao et al., 2012)
Reduced Mouse M Pru (Xiao et al., 2012)
Social interaction Increased Rat n/a RH (Gonzalez et al., 2007)
Associative emotional learning
Passive avoidance test No change Mouse n/a ME49 (Jung et al., 2012)
Fear Conditioning No change Rat M Pru (Vyas et al., 2007)
Impaired Mouse M PLK(II) (Ihara et al., 2016a)
Response to Novelty
Neophobia No change Mouse F Pru (Vyas et al., 2007)
(novel food avoidance)
Anhedonia Reduced Mouse F PLK(II) (Mahmoud et al., 2017, 2016)
Depressive-like behaviour
Forced swim test Increased Mouse F PLK(II) (Mahmoud et al., 2017, 2016)
Static rod test Impaired Mouse F HIF (Hodkova et al., 2007)
Motor control
Locomotor activity-open field No change Mouse M Pru (Xiao et al., 2012)
No change Mouse F ME49 (Kannan et al., 2010)
No change Rat M Pru (Vyas et al., 2007)
No change Rat n/a RH (Gonzalez et al., 2007)
Increased Mouse F Pru (Xiao et al., 2012)
Increased Mouse F Pru (Kannan et al., 2010)
Increased Mouse F HIF (Hodkova et al., 2007)
Increased Mouse F ME49 (Afonso et al., 2012)
Reduced Mouse F GT1 (Xiao et al., 2016b)
Reduced Mouse M ME49 (Gulinello et al., 2010)
Gait and Balance beam Impaired Mouse M ME49 (Gulinello et al., 2010)

(Hidano et al., 2016). These findings were transferable to in vivo mouse
studies, where deletion of STAT1 in astrocytes lead to an increased cyst
count in astrocytes (Hidano et al., 2016), suggesting that astrocyte in-
vasion is possible but astrocytes are able to clear the infection or un-
dergo pyroptosis, and thus cysts are not observed in these cell types in
vivo.
One key question involves the extent of cellular tropism of
Toxoplasma cysts in vivo, and the mechanisms mediating this phenom-
enon. Early studies described the presence of cysts in the brains of in-
fected mice using electron microscopy (EM) techniques (Sims et al.,
1988; Wanko et al., 1962), but failed to demonstrate their cell type
preference conclusively. Nevertheless, one of these studies did observe
that the wall of the tissue cysts contained components derived from the
neuronal cytoskeleton and that intact cysts were separated from the
extracellular compartment by a layer of neurofibrillae enclosed within
the host cell membrane (Sims et al., 1988). This was one of the earliest
indications that cysts within the brain were physically protected from
the host’s immune response. Newer EM techniques revealed that cysts
were predominantly found in the grey matter, were intracellular, and
the majority of the host cells were neurons, as identified by the presence
of synapses (Ferguson et al., 1994; Ferguson and Hutchison, 1987).
More recently, a confocal study in chronically infected mice found that
cysts were almost exclusively present in the neurons, as observed by
encapsulation of cysts by neurofilaments (Melzer et al., 2010).
The tropism for neurons in vivo was elegantly shown by using a
florescent protein expressing Toxoplasma strain (Koshy et al., 2010) and

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Fig. 2. Structural and functional changes in the brain upon Toxoplasma infection. 1. At the macroscopic level, Toxoplasma infection causes lesions in the brain, alters
fibre density and grey matter volume and forms parasite cysts that remain in the brain throughout the lifetime of the host. 2. At the cellular level, the presence of
parasites in the brain parenchyma activates microglia, the immune cells of the brain, that generates the host’s immune response to counteract the invading pathogen.
Such a response is also mediated by the infiltrating T-cells. Infection also leads to a reduced dendritic spine count, causes axonal damage and causes an imbalance in
the proportions of kynurenic acid and quinolinic acid in the neurons. 3. Impairments in brain function can be attributed to changes that occur down at the synaptic
levels in the infected brain. Such changes can be structural, such as synaptic pruning by the classic complement system and altered microtubule and post-synaptic
density organization, or it can be functional, such as imbalance in neurotransmitter synthesis, release, clearance and metabolism, as well as perturbations in
downstream signalling at the post-synapse that lead to changes in gene expression. 5-HT; 5-hydroxytryptamine or Serotonin; BNDF, brain-derived neurotropic factor;
DAPRR-32, Dopamine and cAMP-regulated phosphoprotein, Mr 32 kD; DOP, Dopamine; GABA, Gamma-aminobutyric acid; GABA(A), Gamma-aminobutyric acid
receptor A; GAD67, Glutamic acid decarboxylase 67; GLT-1, Glutamate transporter-1; GLU, Glutamate; GluN1, NMDA receptor subunit N1; GluN2B, NMDA receptor
subunit N2B; IDO, Indoleamine 2,3-dioxygenase; IFNγ, Interferon-gamma; IL, Interleukin; iNOS, Induced nitric oxide synthase; KA, Kynurenic acid; MiR-132,
MicroRNA-132; PSD, Post-synaptic density; QA, Quinolinic acid; VLGUT1, Vesicular glutamate transporter 1.

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exploiting the ability of the parasite to export effector proteins into the
host cells (Boothroyd and Dubremetz, 2008; Bradley and Sibley, 2007).
These parasites injected Cre into the cells of Cre reporter mice, which
enables the visualisation of cells that the parasite has interacted with
allowing the authors to track GFP-positive cells in the brain. These
studies showed that neurons were the primary target cells for Tox-
oplasma and that cysts reside in the cell’s processes rather than at the
cell’s nucleus as seen in vitro (Cabral et al., 2016; Koshy et al., 2012;
Koshy and Cabral, 2014). The most surprising finding using this model
was that Toxoplasma injects proteins into cells that it does not invade.
Overall, the observation that the number of cells affected by Tox-
oplasma (by protein injection) far exceeds cells that actually contain
cysts. The heterogeneity of infection sites observed in vivo indicates that
the parasite could ‘’explore’’ the brain parenchyma before settling on a
host cell and forming a cyst. Deciphering why this occurs could address
how and why Toxoplasma prefer neurons over other cell types and
suggests that this parasite may be able to bring about more distal
changes in the brain that could aid parasite survival and affect neuronal
function behavioural output.
Apart from the cell type, tropism to specific brain region could also
help explain the behavioural consequences. Several studies have tried
to elucidate this parameter, albeit with no conclusive results. An initial
study by Vyas et al. found a mild tropism towards the amygdala, but
cysts were distributed throughout the mouse brain (Vyas et al., 2007).
One study exclusively observed the distribution of Toxoplasma cysts in
the brain of mice with latent toxoplasmosis by hematoxylin-eosin
staining of brain sections and observed no particular tropism. Striking
interindividual differences in the total parasite load and cyst number
and distribution were also observed (Berenreiterová et al., 2011). Using
similar staining techniques, other studies found higher cyst densities in
the cerebral cortex, thalamus and cerebellum in infected rats (Dubey
et al., 2016) and mice (Hermes et al., 2008), while others found no
tropism (Daniels et al., 2014; Gonzalez et al., 2007). Tracking of bio-
luminescent Toxoplasma expressing luciferase under the control of a
bradyzoite-specific gene promoter showed increased luminescence in
the cerebral cortex, colliculi, cerebellum and olfactory bulbs (Di
Cristina et al., 2008). The advent of the cre-injecting line in conjunction
with reporter mice should be able to provide a more definitive answer
to this question whilst also determining if there is any tropism for
specific types of neurons using immunohistochemistry.
3. Behavioural changes in rodents
The majority of the body of work that attempts to answer the basic
questions on how Toxoplasma affects the host behaviour has involved
observing infected rodent models (Table 1). Rodents are intermediate
hosts of Toxoplasma, and changes observed in them perhaps represent
the quintessential characteristics of the proposed ‘manipulation hy-
pothesis’, by which a parasite can manipulate its host’s behaviour in a
way that can increase its transmission into its definitive host. For ex-
ample, Plasmodium infection makes humans more attractive to mos-
quitoes (Koella, 2005; Lacroix et al., 2005; Robinson et al., 2018), ra-
bies increases aggression which is thought to aid more biting (Sapolsky,
2003), and infection by parasitic worm Echinorhynchus truttae increases
the respiratory rate of the fishes, forcing them into regions where they
can be preyed upon (MacNeil et al., 2003). All of these promote
transmission of the infectious agent. Therefore, there is little doubt that
Toxoplasma is also able to affect its host behaviour in an insidious
manner to promote its own selfish means, while at the same time in-
ducing a plethora of related ‘by-product’ neuropsychiatric changes.
Here, we provide an overview of the behavioural changes in rodents
observed upon infection with Toxoplasma.
4. Functional effects on neurons
When evaluating changes in the brain and linking pathogenic events
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Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
to actual onset of neuropsychiatric diseases, the obvious place to look is
the communication between brain cells, and understand the cascade of
events at the molecular level which are translated to global changes in
the brain and dictate behaviour (Fig. 2). Research into various neu-
ropsychiatric conditions aims to do exactly this, and understanding the
effects of Toxoplasma on brain has revealed that many changes observed
during latent infection recapitulate at least some of the effects known to
occur in specific brain disorders.
4.1. Changes in neuronal signalling
Neurotransmitters are chemical messengers in the brain that
transmit signals at synaptic junctions, and are classified into excitatory,
inhibitory or modulatory, depending on their effects on signal trans-
duction, and also have region-specific expressional patterns and func-
tional attributes. Dopamine, a slow-acting modulatory neuro-
transmitter, is essential for long-term regulation of brain functions
(Beaulieu and Gainetdinov, 2011; Girault and Greengard, 2004;
Greengard, 2001). Dopaminergic neurons innervate regions of the brain
chiefly involved with motor function, motivation and working memory
(Beaulieu and Gainetdinov, 2011), and are a central element of the
brain reward system and addiction (Di Chiara and Bassareo, 2007).
Thus, it is not surprising that dopamine dysfunction has been im-
plicated in the aetiology of several human disorders such as Parkinson’s
disease (PD) (Matsumoto, 2015), Alzheimer’s disease (AD) (Martorana
and Koch, 2014), Huntington’s disease (HD) (Cyr et al., 2006; Tyebji
and Hannan, 2017), Schizophrenia (SZ) (Li et al., 2016), Tourette’s
syndrome (Mink, 2006) and attention deficit hyperactivity disorder
(ADHD) (Gizer et al., 2009).
Dopamine dysregulation has perhaps generated the most interest in
the study of Toxoplasma mediated neurochemical changes. Early report
by Stibbs showed higher dopamine levels in chronically infected mice.
This was not the case at acute stages, although the levels of homo-
vanillic acid, a dopamine metabolite, was increased (Stibbs, 1985).
Later in 2009, Gaskell et al. found two genes (aromatic amino acid
hydrolase 1 and 2; AAH1 and AAH2) in Toxoplasma that encoded for
tyrosine hydroxylase (TH) that produces L-DOPA, the precursor of do-
pamine (Gaskell et al., 2009). This was the first study to report the
presence of aromatic amino acid hydroxylase in an apicomplexan
parasite, and gave one of the first evidence of possible direct modula-
tion of neuronal function by the parasite. Reports from the same lab
later showed that presence of Toxoplasma in mammalian dopaminergic
cells enhanced the levels of K+-induced release of dopamine several
fold, and also saw increased staining for dopamine and TH within cysts
present in the brain sections of infected mice (Prandovszky et al.,
2011). A later study by Wang et al. challenged this view by disrupting
the AAH2 gene, whose expression increases at the dormant bradyzoite
stages (Webster et al., 2006), and showed that it had no effects on either
the growth and differentiation of the parasite nor on the global dopa-
mine levels of the brain (Wang et al., 2015). They reported that the role
of AAH genes was to increase the parasite’s capabilities of transmission
in the cat (Wang et al., 2017). This discrepancy between the two la-
boratories was proposed to be due to different methodological ap-
proaches taken (McConkey et al., 2015). More recently, it was shown
that disruption of the AAH2 gene did not alter the parasite induced
behaviour abnormalities (Afonso et al., 2017; McFarland et al., 2018).
Nevertheless, some studies have indeed reported lower dopamine levels
and higher dopamine turnover rates in the brains of mice chronically
infected with Toxoplasma (Ihara et al., 2016b; Kannan et al., 2016;
Mahmoud et al., 2017), but its cause remains elusive.
A mechanism by which Toxoplasma could disrupt dopamine sig-
nalling is by altering microRNA-132 (miR-132) expression. MicroRNAs
are a class of small non-coding RNAs that can regulate gene expression
(Lim et al., 2005), and miR-132 dysregulation is associated with several
neurological disorders such as SZ, AD, and PD (Miller et al., 2012;
Wanet et al., 2012). MiR-132 expression was found to be increased
S. Tyebji et al.
during acute Toxoplasma infection (Li et al., 2015), while a chronic
infection had an opposite effect (Xiao et al., 2014). This effect varied
amongst brain region, was sex-dependent and did not correlate with
density of Toxoplasma in brain regions. Interestingly, when target pre-
diction was performed followed by pathway enrichment analysis in the
transcriptome of Toxoplasma infected mice, dopamine signalling was
the strongest associated pathway regulated by miR-132 expression.
Further, levels of dopamine D1-like receptors, the metabolising enzyme
and intracellular proteins associated with the transduction of dopamine
signalling (DARPP-32 phosphorylation at Thr34 and Ser97) were found
to be decreased as well (Xiao et al., 2014). Thus, although there is no
conclusive evidence of Toxoplasma infection directly increasing dopa-
mine levels in the host cells, sufficient evidence is present to indicate
that dopaminergic pathways are indeed altered and further investiga-
tion in this area is required.
Glutamate is another important neurotransmitter whose metabolism
and signalling is altered upon Toxoplasma infection. Glutamate is an
excitatory neurotransmitter of the CNS and its receptors are localised on
neuronal as well as non-neuronal cells and regulate a broad range of
cognitive processes (Daikhin and Yudkoff, 2000; Dauvermann et al.,
2017; Miladinovic et al., 2015). Under normal physiological conditions,
glutamate is released at the synaptic cleft where it potentiates fast ex-
citatory neurotransmission by activating its ionotropic receptors at the
post synapse, which include the α-amino-3-hydroxy-5-methyl-4-iso-
xazolepropionic acid (AMPA), kainite and N-methyl-D-aspartic acid
(NMDA) receptors and its metabotropic receptors (mGluRs) (Südhof,
2013). At the matured glutamatergic synapses, a steep glutamate con-
centration gradient is maintained at the synaptic cleft by astrocytes at
the synapses that express the sodium-dependent glutamate transporters
and remove excess glutamate after the action potential from the ex-
tracellular field (Daikhin and Yudkoff, 2000). This gradient provides
the driving force for rapid synaptic transmission to occur. Under pa-
thological conditions and dysregulation of the glutamate transporter
expression and/or function, excess extracellular glutamate becomes
neurotoxic by over-activating the ionotropic glutamate receptors,
especially at the extra-synaptic sites, triggering excitotoxic cell death in
surrounding postsynaptic neurons (Choi, 1994).
Altered extracellular glutamate levels upon Toxoplasma infection
has been shown in a recent study (David et al., 2016), while changes in
brain glutamate levels have been reported upon infection with a closely
related parasite Neospora caninum (Ihara et al., 2016a). This report in-
dicates that glutamate homeostasis is disrupted upon infection with
Toxoplasma. David et al. demonstrated that Toxoplasma infection in
mice leads to a gradual reduction in the astrocytic glutamate trans-
porter, GLT-1, in the forebrain (David et al., 2016). In correlation, they
found a significant increase in extracellular glutamate during the
chronic stages of infection. Furthermore, these mice displayed impair-
ments in electroencephalography (EEG) recordings from the frontal
cortex and reduction in anxiety-like behaviour. Interestingly, treatment
with ceftriaxone, a β-lactam that is known to increase GLT-1 expression
(Rothstein et al., 2005), lowered extracellular glutamate and rescued
neuronal pathology, but failed to improve behavioural deficits (David
et al., 2016). In contrast, and probably a hint towards a possible com-
pensatory mechanism, Kannan et al. showed that levels of hippocampal
VGLUT1, a major vesicular glutamate transporter at the excitatory sy-
napse, was reduced in infected mice (Kannan et al., 2016), although
such a change was not observed by another study (Brooks et al., 2015),
and demands more investigation.
But perhaps more important in the glutamate dysregulation model
of Toxoplasma is the role of its ionotropic receptors, specifically the
NMDA receptors (NMDARs). Toxoplasma infection has been strongly
associated with SZ, in light of numerous studies finding increased ser-
oprevalence of toxoplasmosis in individuals with SZ (Arias et al., 2012;
Esshili et al., 2016; Monroe et al., 2015; Sutterland et al., 2015; Torrey
and Yolken, 2003). NMDAR, a key player in the pathophysiology of SZ
(Javitt, 2015, 2010; Moghaddam and Javitt, 2012; Papouin et al.,
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Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
2017), has essentially been proposed as a mechanistic link between
Toxoplasma infection and onset of SZ (Lucchese, 2017; Wang et al.,
2013). Two recent studies by Kannan et al. demonstrate that exposure
to Toxoplasma produces serum IgG antibodies to NMDARs that might
underlie glutamate receptor hypofunction and related impairment
found in SZ. In mice, autoantibodies to GluN2 were elevated when
exposed to live Toxoplasma parasite, but not UV-inactivated parasites
(Kannan et al., 2017, 2016), indicating that antibodies were not pro-
duced to the parasite itself, but involved an antigenic mimic of NMDAR
that is generated during the dormant cyst phase. Interestingly, this in-
crease was more pronounced in juvenile infected mice when compared
to adults (Kannan et al., 2016). Furthermore, evaluation of Toxoplasma-
seropositive individuals with SZ indicated higher NMDA IgG titres
compared to seronegative SZ patients as well as seropositive non-SZ
controls (Kannan et al., 2017). Indeed, a sequence-matching analysis
carried out between seven human NMDAR subunit amino acid se-
quences and the Toxoplasma proteome revealed vast epitopic peptide
sharing between Toxoplasma and NMDAR subunits, indicating that anti-
Toxoplasma immune responses cross-react with NMDARs (Lucchese,
2017). This reaction to Toxoplasma proteins does in fact alter the levels
of NMDA receptors in the cortex and the hippocampus in mice 8 weeks
post infection (Kannan et al., 2016; Torres et al., 2018).
Another interesting neuron modulatory response generated by
Toxoplasma in the brain is its ability to alter GABAergic synapses and
signalling in the CNS. Gamma-aminobutyric acid (GABA), an inhibitory
neurotransmitter, is primarily responsible for preventing the onset of
seizures by modulating the flow and timing of excitatory neuro-
transmission (Treiman, 2001). Essentially, it acts as a tonic brake on the
excitatory tone of glutamate, and as discussed above, perturbations in
glutamate levels and signalling observed in presence of Toxoplasma
could exacerbate any modifications of GABA signalling in the brain.
Epidemiological studies and meta-analysis have indicated that presence
of Toxoplasma in human population is associated with epilepsy (de
Bittencourt et al., 1996; Ngô et al., 2017; Ngoungou et al., 2015;
Palmer, 2007), indicating possible dysregulation of inhibitory neuro-
transmission in the presence of Toxoplasma. GABA is used as a carbon
source by Toxoplasma (MacRae et al., 2012) and infection leads to a
release of GABA from dendritic cells (Fuks et al., 2012). It was de-
monstrated that GABA activated GABA(A) receptors on Toxoplasma-
infected dendritic cells which led to a hypermigratory phenotype in
those cells. This process was postulated as a means of parasite dis-
semination. Further, Brooks et al. recently showed that Toxoplasma
infection in mice leads to spontaneous seizures and re-distribution of
glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalysis
GABA synthesis in the brain, from clustering at pre-synaptic termini, to
a more diffused localization throughout the neuropil (Brooks et al.,
2015). Heteromerisation of GAD67 with GAD65, a membrane an-
choring isoform of glutamic acid decarboxylase, is one of the proposed
mechanism by which GAD67 localises at the pre-synapse (Kanaani
et al., 2010, 1999). Levels of GAD65 have not been studied in Tox-
oplasma infection and remain a plausible explanation for GAD67 re-
distribution. Moreover, GABAergic dysfunction in the prefrontal cortex
is a known signature of major depression (MD) (Croarkin et al., 2011;
Karolewicz et al., 2010; Levinson et al., 2010), a phenotype present in
murine models of Toxoplasma infection (Mahmoud et al., 2017, 2016).
Thus, the association between loss of GABAergic inhibition and Tox-
oplasma-induced behavioural changes needs more investigation.
Serotonin is another neurotransmitter with a role in pathogenesis of
depression (Oxenkrug, 2013) and whose levels are altered upon Tox-
oplasma infection (Ihara et al., 2016b; Kannan et al., 2016; Mahmoud
et al., 2017, 2016; Xiao et al., 2014). Chronic inflammation, as in the
case of toxoplasmosis, pushes tryptophan metabolism towards pro-
duction of kynurenine and away from serotonin, leading to serotonin
deficiency. Indeed, reduced serotonin was found in models of acute
infection or reactivated models of chronic toxoplasmosis, which was
shown to be due to enhanced turnover to its metabolite 5-
S. Tyebji et al.
hydroxyindolacetic acid (Mahmoud et al., 2017, 2016). There are in-
dications that such alterations in serotonin levels could be brain-region
specific, as one study found increased serotonin levels in the striatum
(Xiao et al., 2014), while an earlier study was unable to detect any
serotonin changes in the brain (Stibbs, 1985).
Apart from the canonical neurotransmitter-mediated changes, other
pathways that could directly or indirectly alter brain function and lead
to behavioural changes have also been explored in Toxoplasma infec-
tion. One such pathway is the classical complement system that bridges
innate and adaptive immunity and functions to clear antigen-antibody
immune complexes from systemic circulation (Walport, 2001). This was
first investigated as a likely candidate that could mediate elimination of
Toxoplasma tachyzoites from circulation. On the contrary, studies re-
vealed that although the complement system was activated in presence
of Toxoplasma, it failed to kill the parasites (Fuhrman and Joiner, 1989;
Sacks and Sher, 2002). Interestingly, one study observed that this effect
was specific in the presence of complement in cat sera (Kaneko et al.,
2004). C1q, an immune protein of the classical complement system, is
involved in synaptic pruning and elimination during development as
well as adult neurodegenerative processes (Stephan et al., 2012;
Stevens et al., 2007), and therefore is implicated in the aetiology of
several neuropathological conditions such as AD (Kolev et al., 2009), SZ
(Severance et al., 2014, 2012; Stevens et al., 2007) and multiple
sclerosis (MS) (Michailidou et al., 2015). Recently, it has been reported
that levels of C1q mRNA and proteins are increased in the brains of
Toxoplasma infected mice, and can be found as punctate patterns
around cysts, indicative of synapses along neuronal cell processes
(Kannan et al., 2016; Xiao et al., 2016a). Thus, loss of synaptic com-
plexity could be part of the collateral damage to neurons, due to
complement system activated by the host as a response to pathogen
invasion.
4.2. Toxoplasma – a disease modifier
Emerging studies now posit the presence of Toxoplasma as an en-
vironmental factor that can either act as a trigger for disease onset, a
factor that can exacerbate the disease condition, or sometimes even
ameliorate or halt disease progression. The strongest link is perhaps
between Toxoplasma and the susceptibility of individuals towards de-
velopment of SZ and bipolar disorder (BD), and recent reviews have
discussed this possible connection (Brown and Derkits, 2010; Del
Grande et al., 2017; Elsheikha et al., 2016; Henriquez et al., 2009;
Kannan and Pletnikov, 2012; Sutterland et al., 2015; Yolken et al.,
2009). SZ, affecting about 1% of the world population (Saha et al.,
2005), has major socio-economic impact worldwide, and studies have
consistently shown that the prevalence of Toxoplasma infection is
unusually high in SZ patients (Torrey et al., 2007). Toxoplasma infection
is not only correlated with the appearance of SZ (Ebadi et al., 2014;
Fuglewicz et al., 2017; Torrey and Yolken, 1995; Yolken et al., 2009),
but the effect of latent toxoplasmosis on the risk of developing SZ is
stronger than that of any SZ-associated gene variant identified in
genome-wide analyses (Purcell et al., 2009). Toxoplasma infection was
also shown to exacerbate open field activity in a genetic mouse model
of SZ (Eells et al., 2015) and mimic the depression-like phenotype in a
drug-induced model of SZ (Wang et al., 2013).
A recent study has evaluated the effects of Toxoplasma infection on
aetiology of HD, working on the hypothesis that alterations in the ky-
nurenine pathway, that occur during both Toxoplasma infection (Silva
et al., 2002) as well as in HD (Beal et al., 1992; Thevandavakkam et al.,
2010), could represent a point of synergism between these two condi-
tions (Donley et al., 2016). Indeed, they found that Toxoplasma-infected
HD mice have elevated brain indoleamine 2,3-dioxygenase (IDO) ac-
tivity, and underwent a premature death. Interestingly, Toxoplasma
infection in HD mice produced a blunted CD8+ T-cell IFNγ response as
compared to Toxoplasma-infected wild-type (WT) mice, that lead to an
increased parasite burden in the brain. This is the first indication that
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HD individuals are susceptible to exacerbation of disease phenotype by
Toxoplasma. Nevertheless, its effects on psychiatric changes present in
HD are yet to be explored.
The effect of Toxoplasma on AD is probably quite heterogeneous, in
that the effects of infection depend upon the immune responses due to
interaction between strain of parasite and the genetic mouse model of
AD used in the study. In mice overexpressing a mutant form of amyloid
precursor protein (APP; Tg2576) (Jung et al., 2012) and in mice ex-
pressing mutant APP and presenilin protein-1 (PSEN1; 5xFAD) (Möhle
et al., 2016), Toxoplasma infection leads to a reduction in ß-amyloid
(Aß) plaque burden, possibly due to enhanced production of anti-in-
flammatory cytokines TGF-B and IL-10, and an increase in monocytes
capable of phagocytosing Aß. Interestingly, such neuroprotective ef-
fects led to an improvement in cognitive capacities of AD mice infected
with Toxoplasma (Jung et al., 2012). A later study using the human APP
AD mouse model (J20) determined that only the Type II strain of
Toxoplasma was able to induce the above discussed changes, not Type I
or III (Cabral et al., 2017). On the other hand, reports also suggest that
Toxoplasma infection could exacerbate AD symptoms. One study using a
triple transgenic AD mouse model (3xTg-AD) observed exacerbated
immune response in infected AD mice and severe morbidity (Montacute
et al., 2017). Another study reported an enhancement of cognitive
impairments in infected-BALB/c mice injected with subdoses of Aß
1–42 peptides (1 μl) in the hippocampus and considerable impairments
in learning and memory functions, similar to AD models injected with
2 μl Aß peptides (Mahmoudvand et al., 2016a). More recently, Torres
et al. showed that Toxoplasma infection induces two major hallmarks of
AD such as Aß immunoreactivity and hyperphosphorylated Tau (Torres
et al., 2018). It is noteworthy that complement component C1q, acti-
vated upon Toxoplasma infection (Xiao et al., 2016a), can initiate mi-
croglia-mediated synaptic loss (Fonseca et al., 2004; Hong et al., 2016)
as well as phagocytosis of pre-amyloid aggregates providing neuro-
protection in AD (Pisalyaput and Tenner, 2008). This confounding role
of the complement system in AD pathology could explain the incon-
sistent results discussed above and therefore, more thorough and con-
clusive results are required to assess the susceptibility of AD patients to
Toxoplasma infection.
5. Neuropathology of infection
Changes in structure and morphology of neurons is a common
phenomenon in neuropsychiatric diseases. Morphological integrity of
neurons dictate its function by establishing synaptic partnerships, and
thus it is no surprise that any change that compromise its structural
rigour could have direct implications on how the cells respond to sti-
muli i.e. affect learning and memory. Behavioural changes in
Toxoplasmosis have thus led to studies that analyse if neuronal integrity
is compromised, or the damage is also taken even further so as leading
to cell death.
Toxoplasma infection causes significant neuronal pathology, and few
recent studies have demonstrated this in vivo as well as in vitro (Fig. 2).
More recently, in vivo non-invasive magnetic resonance imaging (MRI)
was performed at high magnetic fields on Toxoplasma infected mice
which identified and anatomically localised the preferential lesion sites
of parasite-induced brain pathology (Parlog et al., 2014). High density
of hypointense lesions were found in the somatosensory and motor
cortices, hippocampus and the striatum of all the infected mice. Fur-
ther, a detailed qualitative and quantitative analysis of the brain con-
nectional microstructure using in vivo diffusion-tensor MRI and high-
resolution fiber mapping revealed that the somatosensory cortical re-
gions showed the highest density of lesions, and a loss in fiber co-
herence and density at the lesion sites (Parlog et al., 2014). Such fiber
density maps showed an overall fiber loss in the infected group. Inter-
estingly, a voxel-based morphometry MRI in schizophrenic individuals
positive for IgG against Toxoplasma revealed significantly reduced grey
matter volume of several cortical regions compared to non-infected
S. Tyebji et al.
patients (Horacek et al., 2012). Above studies indicate that apart from
local neuronal changes, alterations in intra-regional brain connectivity
might also play a significant role in the observed behavioural outcomes.
When individual neurons were analysed, Parlog et al. observed
significantly reduced dendritic complexity of the layer II/III pyramidal
neurons of the cortex, the CA1 pyramidal neurons as well as the granule
cells of the dentate gyrus of the hippocampus (Parlog et al., 2014).
Total dendritic length was reduced only for the layer II/III and the
granule cells. Reduced dendritic complexity was also reported in a more
recent study where dendritic spines from the frontal cortex were
quantified using dil labelling in frozen sections from naïve and infected
mice (David et al., 2016). Dendritic spines are specialised membrane
protrusions from a neuronal dendrite that receive synaptic input from
the neighbouring neurons (Blanpied and Ehlers, 2004). Abnormalities
in dendritic structure and number are a characteristic observed in
several neuropsychiatric disorders (Glantz and Lewis, 2000; Qiao et al.,
2017; Tyebji and Hannan, 2017; van Spronsen and Hoogenraad, 2010).
An initial study by Mitra et al. showed that the total dendritic length of
the principal neurons of the basolateral amygdala (BLA) were reduced
in rats 8 weeks after infection (Mitra et al., 2013). While both the
hemispheres were affected, the right hemisphere showed a greater
dendritic retraction. Interestingly, when such an analysis was done in
the neighbouring brain region, the pyriform cortex, dendritic retraction
was not observed. This precluded a generalised retraction across the
brain, and is indicative of brain region specific effects of toxoplasmosis.
Weather such effects are a result of a differential response of particular
neurons to the infection remains to be discovered.
Neuronal architecture is maintained by the cytoskeletal structure of
the cells and Toxoplasma infection also causes disruption in neuronal
cytoskeleton which have been mapped in some recent studies. In one
model of murine toxoplasmosis, infection with ME49 type II strains led
to a significant reduction in the neuronal neurofilament marker SMI311
along with reduction in microtubule associated protein-2 (MAP2) in the
somatosensory cortex (Parlog et al., 2014). Staining for β-III tubulin, a
component of neuronal cytoskeleton, revealed a disruption in the
neuronal structure, with mice infected with ME49 strains displaying a
reduced number of β-III tubulin positive cells in the layer II/III of the
cortex (David et al., 2016). In the same study, damage to neurons was
also observed via a significant reduction in staining for the neuronal
nuclei marker NeuN. Interestingly, such a reduction in neuronal mar-
kers was not due to a reduction in total cell count, as Nissl staining
revealed no significant changes in cell density. Further, Toxoplasma
infection in a mouse model of AD blocked neurodegeneration and re-
duced amyloid plaque formation in the cortex and hippocampus com-
pared to their non-infected counterparts (Jung et al., 2012). Above ef-
fects could be explained by studies that show that during latent
infections, Toxoplasma contributes to control the host immune system
in a way that prevents neurodegeneration (Rozenfeld et al., 2005, 2003;
Wagner et al., 2009), possibly via the production of transforming
growth factor ß-1 secreted by IFNγ-activated microglia (Rozenfeld
et al., 2005). On the contrary, it is interesting to note that cell death was
observed in vitro in mouse neuronal cells co-cultured with Toxoplasma-
infected microglial cell as well as in vivo in mouse models of tox-
oplasmosis encephalitis (TE) (Zhang et al., 2014). Such model of re-
activated toxoplasmosis is particularly relevant to im-
munocompromised individuals or those on continuous
immunosuppressive medication due to its devastating effects on the
brain (Dellacasa-Lindberg et al., 2011; Jones et al., 1996; Reiter-Owona
et al., 2000). This effect was due to microglial activation and sub-
sequent release of pro-inflammatory cytokines, because an inhibitor of
microglial activation blocked the above described effects (Zhang et al.,
2014). The effects on Toxoplasma in vitro are indeed different in terms of
survival and function.
In toxoplasmosis, cell death can occur due to the fact that
Toxoplasma infection leads to a robust induction of pathways associated
with excitotoxicity (Cervenka et al., 2017; Lucchese, 2017; Mizuno
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Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
et al., 2008) and also because programmed cell death is an essential
mechanism of the host to combat infectious diseases (Contreras-Ochoa
et al., 2013; Graumann et al., 2009). Possible excitotoxic mechanisms
associated with Toxoplasma infection is discussed in detail in Section 6.
The general lack of cell death in vivo could be due to the strategies
evolved by Toxoplasma to directly inhibit host cell apoptosis in order to
hamper elimination (Contreras-Ochoa et al., 2013; Graumann et al.,
2009; Ni Nyoman and Lüder, 2013; Payne et al., 2003). These include
upregulation of the anti-apoptotic mechanism in host cells such as re-
duction or inhibition of caspase molecules, upregulation of anti-apop-
totic factors and downregulation of poly ADP-ribose polymerase ex-
pression (Goebel et al., 2001; Kim and Denkers, 2006). This effect is not
only induced in infected cells, but neighbouring cells as well (Orlofsky
et al., 2002; Vutova et al., 2007), possibly contributing to protecting the
brain from neurodegenerative events. Although, recently a study
showed increased cell death in the cortex and olfactory bulb of mice 60
days after infection (Torres et al., 2018).
Apart from changes in cell structure, Toxoplasma infection has also
been reported to alter neuronal structure and function at the synaptic
level. Synapses are the units of information processing in the brain, and
they play a dynamic role in learning and memory processes by being
modified in structure and function upon receiving external stimuli and
environmental cues. Post-synaptic density protein-95 (PSD-95) main-
tains the correct molecular organisation of the postsynaptic density
complex (Chen et al., 2011) and regulates synaptic plasticity
(Montgomery and Madison, 2004). At the pre-synapse, synaptophysin
modulates vesicle cycle and neurotransmitter release at the synaptic
cleft (Valtorta et al., 2004). Thus, predictably, dysregulation of these
important synaptic proteins have major implications for the beha-
vioural outcome of the animal (Deng et al., 2012; Irie et al., 1997;
Newpher and Ehlers, 2008; Schmitt et al., 2009). Indeed, upon infection
with Toxoplasma, a significant reduction in PSD-95 and synaptophysin
was observed in the hippocampus and cortex of mice 8 weeks later
(Kannan et al., 2016; Parlog et al., 2014). Whether such changes in
synaptic protein precede abnormalities observed in the dendritic com-
plexity during chronic toxoplasmosis remain to be studied.
6. The brain – immune axis
The brain has classically been accepted as an immune privileged
organ due to the lack of the classical lymphatic system draining CNS
antigens and the tight capillary junctions of the BBB that limits the
entry of immune cells into the brain parenchyma, as well as astrocyte
endfeet processes. Although this notion still holds true, it has been in-
creasingly accepted now that immune cell infiltration of the CNS occurs
not only during infection to control pathogenic invasion but also to
maintain brain homeostasis and function (Carson et al., 2006; Kipnis,
2016; Louveau et al., 2015). Such neuroimmune interactions can have
both beneficial and detrimental effects on brain functions. Even before
reaching the brain, peripheral immune activation caused by Toxoplasma
can produce a host of pro-inflammatory immune cells that can cause
neuroinflammation, leading to local or global disruption in neuronal
physiology (Filiano et al., 2015). Interestingly, peripheral immune
mediators have been implicated in the pathophysiology of SZ, HD, MD,
AD, stroke, autism as well as traumatic brain injury (TBI) (Carter, 2011;
Haroon et al., 2012; Onore et al., 2012; Zheng et al., 2015). Discussing
every effector cell/molecule activated in the central and peripheral
immune system upon Toxoplasma infection is beyond the scope of this
review article, and has been discussed elsewhere (Aliberti, 2005; Klein
et al., 2017; Yarovinsky, 2014). Instead, here we shall discuss changes
in immune and hormonal milieu after Toxoplasma infection which di-
rectly or indirectly impinge on the brain function that might result in
alterations in cognitive abilities of the host.
IFNγ production represents the first line of defence against
Toxoplasma infection when innate immune cells such as dendritic cells
(DC) and neutrophils, and macrophages via IL-10 release, initiate
S. Tyebji et al.
natural killer (NK) cell and T-cell mediated IFNγ production (Denkers
et al., 2004; Hunter et al., 1996). In the brain, invasion by Toxoplasma
leads to rapid expression of chemoattractant such as CCL5, CXCL9 and
CXCL10 by astrocytes and microglia that recruit IFNγ producing CD8+
and CD4+ T-cells directed at Toxoplasma antigens, leading to parasite
clearance (Landrith et al., 2015). Also, Toxoplasma infected CNS shows
increased astrocytic expression of TNF, IL-1B and IL-6 (Mahmoudvand
et al., 2016b). It is noteworthy that each of these effector molecules has
been implicated in altering neural correlates that are involved in
memory formation such as neurogenesis, synaptic plasticity and mod-
ulation of long-term potentiation (del Rey et al., 2013; Filiano et al.,
2016; Mandolesi et al., 2017; Riazi et al., 2015; Wu et al., 2013). IFNγ
has an important role in regulating social behaviour, anxiety- and de-
pressive-like behaviour as well as spatial recognition memory, and
dysregulation of these has been associated with Toxoplasma infection
(Gonzalez et al., 2007; Goodwin et al., 2012; Mahmoud et al., 2017,
2016). Interestingly, results show that increase in IFNγ signalling has
positive and reinforcing roles on social behaviour (Filiano et al., 2016),
but caused affective dysfunction in mice (Mandolesi et al., 2017). Fi-
liano et al. demonstrated that IFNγ knock-out mice (KO) displayed so-
cial deficits, that could be rescued by a single injection of IFNγ (Filiano
et al., 2016). Also, IFNγ increased tonic GABAergic inhibitory current,
increased latency to reach seizures, and reduced the maximum severity
of seizures. Moreover, diazepam, a GABA activator, rescued social
deficits in IFNγ KO mice. These results demonstrate that IFNγ mediates
GABAergic signalling, that regulates social behaviour in mice. Given
that Toxoplasma infection leads to redistribution and dysregulation of
GABA in the brain (Brooks et al., 2015), this could impair IFNγ medi-
ated social activity in infected mice. Another study found that IFNγ KO
mice displayed increased anxiety- and depression-like phenotype, with
reduced neurogenesis in the hippocampus (Campos et al., 2014). It is
interesting to note that, although IFNγ KO mice displayed impaired
spatial recognition memory in basal state, under conditions of chronic
stress, IFNγ KO mice displayed enhanced memory performance
(Litteljohn et al., 2014). This indicates that IFNγ signalling, under
conditions of chronic stress such as in Toxoplasma infection, exacerbates
memory impairments. Indeed, recently it was shown that in models of
experimental autoimmune encephalomyelitis (EAE), increase in IFNγ
signalling in the striatum caused anxiety- and depressive-like beha-
viours in mice (Mandolesi et al., 2017). This occurred by dysregulation
of the cannabinoid CB1 receptor at the GABAergic synapses in the
striatum. Thus, the direct role of IFNγ signalling in regulating memory
performance in infected mice requires a thorough inspection. Never-
theless, downstream effectors of IFNγ signalling, generally studied as
part of IFNγ mediated mechanism of parasite killing, are also involved
in memory regulation and their effects on regulating host behaviour
seem more plausible under conditions such as Toxoplasma infection.
One mechanism by which IFNγ suppresses Toxoplasma growth is by
inducing tryptophan degradation via IDO activation (Pfefferkorn, 1984;
for other mechanims see: Hunter and Sibley, 2012). Tryptophan is an
essential amino acid and a precursor for the synthesis of serotonin. Also,
IDO can cleave the indole ring of serotonin to form its breakdown
product formyl-5-hydroxykynurenamine (Steiner et al., 2011). Thus,
IFNγ induction could lead to changes in serotonin metabolism, and its
effects have been discussed earlier. Tryptophan metabolism also in-
duces the kynurenine pathway, whose end products are the two neu-
rotoxic agents, kynurenic acid (KA) and quinolinic acid (QA) (Ruddick
et al., 2006). Under basal conditions, most kynurenine is metabolized to
KA (Hilmas et al., 2001), but under inflammatory conditions, kynur-
enine metabolism shifts towards QA production (Saito et al., 1992). QA,
an NMDA agonist, is heavily implicated in driving glutamate mediated
excitotoxicity as well as precipitating oxidative damage in neurons,
which is now well documented as a precursor for development of
neuropsychiatric disorders (Lugo-Huitrón et al., 2013). Indeed, higher
KA levels are a characteristic of SZ (Erhardt et al., 2001; Nilsson et al.,
2005; Schwarcz and Hunter, 2007), while QA upregulation has been
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implicated in the aetiology of AD (Gulaj et al., 2010), HD (Guidetti
et al., 2006, 2004), depression (Steiner et al., 2011), autism
(Zimmerman et al., 2005), as well as in cases of increased suicidal at-
tempts (Erhardt et al., 2013). Interestingly, activation of the kynurenine
pathway is observed in the brains of Toxoplasma infected mice, as
measured by increased IDO production, kynurenine metabolism and QA
levels (Murakami et al., 2012; Notarangelo et al., 2014; Silva et al.,
2002). Many recent studies have shown that activation of IDO, likely
via disruption in kynurenine metabolism pathway and subsequent QA
production and NMDAR-mediated excitotoxicity, leads to depression-
like phenotype observed in Toxoplasma infected mice (Dinel et al.,
2014; Mahmoud et al., 2017; Mazarei et al., 2013; Parrott et al., 2016).
The changes in NMDAR signalling, PSD organization as well as altera-
tions in receptor levels discussed before could be an outcome of Tox-
oplasma-mediated changes in the kynurenine pathway. Further studies
are required to ascertain the role of kynurenine pathway in Toxoplasma
infection and if such changes are associated with onset and/or ex-
acerbation of neuropsychiatric conditions already displayed by pa-
tients.
Another downstream effector of IFNγ signalling and an important
microbicidal mechanism for the control of Toxoplasma infection is NO
generated by the action of nitric oxide synthase (NOS). Depending on
the site of expression, NOS has three isoforms: endothelial (eNOS, ex-
pressed in vascular endothelium and choroid plexus), neuronal (nNOS,
expressed in neuronal cell bodies) and inducible (iNOS, expressed in
macrophages and glial cells). Interestingly, all three isoforms are pro-
duced in the brain of mice in response to Toxoplasma infection (Dincel
and Atmaca, 2015; Tonin et al., 2014). NO production upon Toxoplasma
infection has a protective role by killing and eliminating the parasites
(Khan et al., 1997), and thus it is no surprise that Toxoplasma activity
inhibits NO production to better its odds of survival (Guillermo and
DaMatta, 2004; Seabra et al., 2002). In fact, recent attempts at pro-
ducing vaccines against the parasite exploit this protective NO me-
chanism to reduce brain parasitism (Czarnewski et al., 2017). However,
although NO production helps the host cells control parasite pro-
liferation, it has a detrimental, sometimes lethal effect on the cells as
well as the infected mice. iNOS KO mice had a higher brain cyst burden
(Sa et al., 2017), but much lower brain inflammation than their par-
ental lines, with no change in IFNγ or TFNα levels (Khan et al., 1997).
Despite increased proliferation of Toxoplasma in the brains of iNOS KO
mice, these mice displayed increased survival post-infection (Khan
et al., 1997). Thus, NO production plays an important role in regulating
parasitism in the host.
Apart from its microbicidal function, NO also signals as a neuro-
transmitter in the brain, and has not only been implicated in processes
that regulate learning and memory (Paul and Ekambaram, 2011;
Steinert et al., 2010) but also in brain homeostasis by regulating cere-
bral blood flow at rest and under physiological conditions (Garry et al.,
2015). NO is synthesized in the brain on demand upon neuronal activity
under cognitive conditions, when an increase in intracellular Ca2+
leads to the activation of eNOS or nNOS leading to NO creation, while
Ca2+-independent induction of NO by iNOS mediates immune function
(Steinert et al., 2010). Interestingly, NO derived from eNOS and nNOS
is neuroprotective and facilitates synaptic plasticity, while NO derived
from iNOS may have neurotoxic effects. Under physiological condi-
tions, levels of iNOS in brain and vasculature is low (Ortiz and Garvin,
2003), but under conditions of inflammation, such as upon Toxoplasma
infection, iNOS levels are upregulated (Fujigaki et al., 2003), which
might lead to nitrostative stress: this is the ability of NO and its deri-
vatives (reactive nitrogen species) to cause damage to lipids, proteins
and DNA, leading to neuronal toxicity (Beckman and Koppenol, 1996).
Another detrimental consequence of increased NO is the inhibition of
the mitochondrial respiratory chain leading to oxidative stress
(Erusalimsky and Moncada, 2007; Heales et al., 1999). NO production
due to inflammation and resulting oxidative stress has been implicated
in the aetiology of AD, PD, MS and HD, as well as brain damage
S. Tyebji et al.
following ischemia and reperfusion (Bennett et al., 2009; Steinert et al.,
2010). Increased iNOS expression and axonal damage was reported in
experimental models of PD (Barthwal et al., 2001; Gatto et al., 2000;
Singh et al., 2005), as well as post-mortem brain tissues from patients
with MS (Bö et al., 1994), AD (Wallace et al., 1997) and PD (Hunot
et al., 1996). Thus, the above discussed data strongly suggests that upon
infection with Toxoplasma, the interplay among different isoforms of
NOS might play a pivotal role in determining its effects in the brain, and
a balance between anti-parasitic and pro-cognitive properties of NO
signalling and detrimental cytotoxic properties of NO and its deriva-
tives requires a further detailed investigation and understanding.
Cytokines such as IL-1ß, IL-6, IL-1 and TNFα, all of which are
known to be produced in abundance upon Toxoplasma infection (Burke
et al., 1994; Hunter et al., 1992a, 1992b), activate the hypothalamic-
pituitary-adrenal (HPA) axis (Tilders et al., 1994; Turnbull and Rivier,
1995), an essential adaptive mechanism to stressful environment
(López et al., 1999). HPA activation leads to secretion of corticosterone
(CORT) that mediates emotional (Pariante and Lightman, 2008), an-
xiety (Mitra and Sapolsky, 2008) and depressive-like behaviour
(Johnson et al., 2006), possibly involving serotonin signalling in the
amygdala (Herman et al., 2003; Mitra et al., 2009a;b). Interestingly, it
was demonstrated that Toxoplasma infection leads to reduction in basal
CORT levels as well as CORT in response to stressful stimuli such as
exposure to cat odour (Mitra et al., 2013). This could possibly explain
the loss of fear to cat odours, but characterizing other behavioural
changes in Toxoplasma-infected mice has indicated an increase in an-
xiety and depressive-like phenotypes (Gatkowska et al., 2012;
Mahmoud et al., 2017, 2016; Skallová et al., 2006), indicating me-
chanisms separate from HPA-axis- mediated signalling.
Thus, activation of the central and peripheral immune system in
response to parasitic infection is a ‘slippery slope’ that allows the brain
to control parasitism but leads to unintended changes in neuronal
function, manifesting as neuropsychiatric problems.
7. Implications for human behaviour and brain disorders
Toxoplasma infection has major implications on our society and
global healthcare systems. Humans are secondary hosts in the trans-
mission cycle of Toxoplasma in the environment and its effect on human
personality and behaviour are wide ranged and mostly subtle (Flegr,
2013; Sugden et al., 2016). In Toxoplasma-infected human subjects,
characterizing the personality profile has revealed several changes in
their psychology, some based on their gender. Infected men were found
to be more suspicious and jealous, and had higher tendency to disregard
rules (Flegr, 2007). Meanwhile, infected women were more easy-going
and warm-hearted than their uninfected counterparts. Further, both
men and women showed reduced novelty-seeking behaviours (Flegr,
2010; Flegr et al., 2003; Skallová et al., 2005), were more submissive in
a conflict and had a blunted reflex behaviour under imminent danger,
while reporting that diplomacy is not their strong point (Flegr, 2010).
In terms of behavioural changes, there have been some association
studies linking Toxoplasma infection to depression (Gale et al., 2014;
Pearce et al., 2012) and epilepsy (de Bittencourt et al., 1996; Ngoungou
et al., 2015; Palmer, 2007), while one case report also suggested that
depressive-like symptoms could be alleviated upon successful Tox-
oplasma treatment (Kar and Misra, 2004). Infection was also correlated
with depression in pregnant women (Nourollahpour Shiadeh et al.,
2016). Toxoplasma infected subjects showed prolonged reaction times
measured by a simple reaction test (Havlícek et al., 2001). Performance
worsened proportional to the levels of anti-Toxoplasma antibodies and
tests suggested that toxoplasmosis impaired long-term concentration
ability rather than maximum performance. Also, such an impaired
psychomotor performance, along with slower reaction times (Havlícek
et al., 2001; Příplatová et al., 2014) and poor attention (Beste et al.,
2014), could explain the increased incidence of Toxoplasma infected
drivers to be involved in road traffic accidents (Flegr et al., 2009;
82
Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
Kocazeybek et al., 2009; Yereli et al., 2006). Other documented changes
in human traits upon infection with Toxoplasma were poor impulse
regulation in males and violent and risk-taking behaviour along with
self-directed violence in women (Cook et al., 2015; Pedersen et al.,
2012). Also, some studies have found an increased association between
Toxoplasma antibody titer and suicide attempts (Arling et al., 2009;
Ling et al., 2011; Yagmur et al., 2010). Moreover, population com-
parison studies have documented a correlation between Toxoplasma
antibody titers to increased homicide and suicide (Lester, 2012, 2010),
in line with another study that reported higher seropositivity among
prison inmates (Alvarado-Esquivel et al., 2014). In order to make this
data more definitive, longitudinal studies are required that evaluates
the mental health status of people before and after acquiring infection.
Moreover, monitoring the infection status should be made a routine for
mental health patients, which could possibly uncover previously un-
known effects of Toxoplasma on human behaviour.
8. Transgenerational influence of Toxoplasma
The most prominent deleterious effect of acquiring Toxoplasma in-
fection during pregnancy is its effects on the offspring. The effects of
maternal immune activation on offspring mental health is a widely
studied field of research (Canetta and Brown, 2012; Knuesel et al.,
2014), and thus it is no surprise that Toxoplasma infection in utero is
associated with high risk of developing psychiatric diseases, by af-
fecting fetal brain development and increasing the vulnerability to
develop SZ later in life (Brown et al., 2005; Elsheikha et al., 2016;
Mortensen et al., 2007a, 2007b). Studies that document specific can-
didate infections associated with the incidence of neuropsychiatric
disorders have shown high predilection between prenatal Toxoplasma
infection and SZ (Brown et al., 2009; Brown and Derkits, 2010). It is
noteworthy, however, that SZ was shown to relate to high maternal
Toxoplasma IgG levels and not the presence of parasite itself (Brown
et al., 2000; Mortensen et al., 2007a). However, no association was
found between maternal Toxoplasma infection and risk of BD
(Freedman et al., 2016; Mortensen et al., 2011), suggesting that effects
of Toxoplasma infection may be specific to development of SZ. Studies
on mouse models of congenital Toxoplasma infection indicated that
infection acquired during gestation or prior to mating resulted in off-
spring that displayed increased ambulatory activity and reduced pre-
ference for novelty (Hay et al., 1984) and learning and memory deficits
(Wang et al., 2011). However, a later study failed to confirm these
findings, and moreover reported that maternal Toxoplasma infection
does not result in neurotransmitter changes in offspring brain (Goodwin
et al., 2012). It is likely that changes observed upon maternal Tox-
oplasma infection could be due to exposure to inflammatory environ-
ment during development, rather than a direct effect of parasite IgG or
the parasite itself. Indeed, maternal inflammation leads to changes in
anxiety and performance in spatial learning tasks in the offspring
(Schaafsma et al., 2017), and also activates maternal complement C1q
system, a risk factor in the development of SZ and psychosis in offspring
(Severance et al., 2014). Apart from the development of neu-
ropsychiatric disorders in offspring, maternal infection with Toxoplasma
causes spontenous abortions (Giakoumelou et al., 2016; Jones et al.,
2001; Wong and Remington, 1994) and lower body weight at birth
(Wong and Remington, 1994) is associated with harm to the developing
fetus due to an increased risk of self-directed violence in pregnant fe-
males (Pedersen et al., 2012).
Inheritance of Toxoplasma effects via the paternal line of transmis-
sion has recently gained attention. Rodent studies have shown that
males infected with Toxoplasma display reduced sexual rigor, reduced
sperm motility, sperm count and viability and increased sperm defor-
mities (Abdoli et al., 2012; Dalimi and Abdoli, 2013; Dvorakova-
Hortova et al., 2014; Lim et al., 2013; Terpsidis et al., 2009). Mating
with infected males resulted in a significant drop in successful preg-
nancies (Asgari et al., 2015). Interestingly, Toxoplasma parasites were
S. Tyebji et al.
detected in the semen of infected human, rat, rabbit, dog, sheep, cattle,
goat, and swine (Dalimi and Abdoli, 2013; Flegr et al., 2014), while in
some species such as rabbit, sheep, and dogs, Toxoplasma can also be
transmitted via semen to infect the females during mating (Flegr et al.,
2014), but such a phenomenon has not yet been found in mice (Asgari
et al., 2015). Thus, Toxoplasma indeed affects the male reproductive
parameters, but does it have any effects on the next generation?
There has been only one study conducted on human population that
reported that fathers of congenitally infected infants were also more
likely to be seropositive for Toxoplasma infection. (Contopoulos-
Ioannidis et al., 2015). However, what is more important in this context
is the effect of parasite infection on the epigenetic changes that can be
transmitted from father to offspring via sperm resulting in behavioural
changes. Indeed, Toxoplasma infection has been reported to induce al-
terations in DNA methylation status of genes in the brain (Hari Dass and
Vyas, 2014) as well as promoters of spermatogenesis genes (Dvorakova-
Hortova et al., 2014). It is noteworthy that multiple studies have re-
ported that paternal exposure to stress results in epigenetic changes in
sperm small non-coding microRNAs that can transmit experience-de-
pendent information from parent to offspring and results in detectable
changes in behavioural phenotype up to three generations (Bale, 2015;
Short et al., 2016; Yeshurun et al., 2017; Yeshurun and Hannan, 2018).
Microinjection of specific sperm microRNAs, known to be modified
upon paternal stress experience, into the zygote recapitulated stress
dysregulation phenotype in the offspring (Rodgers et al., 2015). What is
yet unknown is whether Toxoplasma’s presence in the testis and semen
somehow reprograms or establishes epigenetic marks in the father’s
germ line which is inherited by the offspring. Such investigations would
open up a whole new arena of congenital toxoplasmosis, with major
public health implications.
9. Host-parasite interactions
Alternatively, the changes discussed above could occur as a result of
active manipulation by the parasite. Toxoplasma is known to manip-
ulate the host response during an acute infection by actively exporting
proteins (Coffey et al., 2016), to prevent clearance and thus enabling
the establishment of a chronic infection. Toxoplasma appears to have
two pathways which it can export proteins into the infected host cell or
at the host parasite interface, both of which are immunomodulatory.
Invading tachyzoites inject proteins from unique secretory organelles
shared by related parasites known as ‘rhoptries’ (Boothroyd and
Dubremetz, 2008; Bradley and Sibley, 2007). Rhoptries inject several
known proteins, including a fascinating group of kinases and pseudo
kinases, which are involved in initial immune evasion (Clough and
Frickel, 2017; Delorme-Walker et al., 2012; Peixoto et al., 2010; Saeij
et al., 2007). One of the most interesting findings regarding host cell
manipulation by Toxoplasma was the discovery that, in the brain, the
parasite will also inject proteins into cells that it does not invade (Koshy
et al., 2012). These ‘injected but uninfected’ neurons outnumbered in-
fected cells suggesting that parasites can move through the brain par-
enchyma and modify surrounding host cells without directly invading
them. This potentially has an impact on avoiding immune clearance
and may also be important for eliciting changes in neurons, causing
brain dysfunction.
Once the parasites have invaded, concomitantly generating a va-
cuole (parasitophorous vacuole; PV) that separates it from the host
cytoplasm, it induces the expression of a second round of effector
proteins. These proteins are exported via dense granules (DG) orga-
nelles into the host cell or become embedded in the PV membrane
(PVM). The DG proteins (GRA) are associated with the maturation of
PV/PVM as well as the modulation of the host cell in order to manip-
ulate the immune signalling and upregulate host pro-survival pathways
(Clough and Frickel, 2017; Mercier and Cesbron-Delauw, 2015). Four
DG proteins identified to date manipulate host pathways, which result
in an altered immune response and changes to cell survival pathways
83
Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
(Bougdour et al., 2013; Braun et al., 2013; Franco et al., 2016; Gay
et al., 2016; Nadipuram et al., 2016).
One of the first nuclear DG proteins to be characterized was GRA16,
which alters the expression of proteins involved in the cell cycle
(Bougdour et al., 2013). Once exported, GRA16 interacts with tran-
scription factors and p53 regulators, thus preventing apoptosis and
causing cell cycle arrest (Bougdour et al., 2013; Li et al., 2002). Further
analysis identified GRA24, a protein that localizes to the host nucleus
where it forms a complex with p38α mitogen-activated protein kinase
(MAPK), inducing its auto-phosphorylation independently of the MAPK
cascade (Braun et al., 2013). This resulted in significant upregulation of
pro-inflammatory cytokines such as IL-12, TNF, and IFNγ. Furthermore,
the prolonged nuclear localisation of the GRA24-p38α complex led to
an increased expression of immediate early gene products such as of
Egr-1 and c-Fos, resulting in a wave of downstream transcriptional
changes (Braun et al., 2013).
The ability to respond to IFNγ and initiate STAT1-dependent tran-
scription is vital to TH1 defence against Toxoplasma. It has been known
for some time that Toxoplasma suppresses STAT1 dependent tran-
scription, despite normal STAT1 activation and nuclear localization in
response to IFNγ (Kim et al., 2007; Rosowski et al., 2014; Rosowski and
Saeij, 2012). The DG protein IST (Inhibitor of STAT1 Transcriptional
activity) was identified and was found to localise at the host nucleus,
were it inhibits STAT1 transcription, not by preventing its DNA binding
capacity, but rather increasing it (Gay et al., 2016; Olias et al., 2016;
Rosowski et al., 2014). The mechanism by which IST increases STAT1-
DNA binding and mediates the repression of transcription is two-fold:
(1) by increasing the phosphorylation of STAT1 and therefore acti-
vating and localising additional STAT1 to the nucleus, all in the absence
of IFNγ, and (2) by recruiting the chromatin remodelling complex (Mi-
2/NuRD) to the GAS (interferon gamma activated sequence) site, re-
sulting in histone acetylation modification and inactivation. In contrast
to the proteins described above, DG protein, GRA15, does not localise at
the host nucleus, but rather it is thought to be embedded into host-side
of the PVM where it activates the host’s NF-kB pathway by the nuclear
translocation of NF-kB subunit, p65 (Rosowski et al., 2011).
Translocation of all these factors across the vacuolar membrane and
into the host cell requires machinery. A parasite Golgi-resident protease
(ASP5) has been shown to be required for maturation of exported
proteins (Coffey et al 2015, Hammoudi et al., 2015, Curt-Varesano et al
2015, Gay et al., 2016). Further, translocation complex comprising
MYR1, 2 and 3 is essential for Toxoplasma proteins to cross the va-
cuolar membrane into the host cell (Franco et al., 2016; Marino et al.,
2018). Removal of any of this translocation machinery has drastic ef-
fects on parasite-induced changes to host cell transcription (Naor et al.,
2018).
To date, the majority of research into host-Toxoplasma interactions
has focussed on the tachyzoite stage of the lifecycle. However, there is
no evidence to show that encysted bradyzoites export proteins and
whether these factors, if any, are the same or different to that known to
be exported by tachyzoites. Nevertheless, it seems unlikely that the
parasites in bradyzoite stages can remain concealed from the immune
system without some kind of host manipulation. Furthermore, many of
the pathways modulated by tachyzoites, such as the MAPK, IFNγ, and
NF-kB pathways, have been implicated in important neuronal functions
and behaviours. To simply ignore the function of the bradyzoites, and
their potential role in neuropsychiatric diseases and mental health,
would give us an incomplete picture of the successful lifecycle this
parasite has evolved in order to survive and spread. Manipulating the
behaviour of the infected host to promote transmission is an observed
characteristic in many parasitic infections (Koella, 2005; Lacroix et al.,
2005; MacNeil et al., 2003; Sapolsky, 2003), but whether such ma-
nipulation is a direct result of parasite molecules or due to an indirect
effect of the immune response against Toxoplasma in the brain remains
unclear. Distinguishing between events occurring in tachyzoite and
bradyzoite stages, and understanding host immune responses, is critical
S. Tyebji et al.
to elucidate links between Toxoplasma infection and mental health. It
may also provide insights into how environmental factors (such as in-
fection), internal factors (the immune response) and genetics of the
host, interact to affect an individual’s health.
10. Countermeasures for effects on the brain
Studies have tried to investigate the anti-Toxoplasma effect of anti-
psychotic drugs, with an aim to counteract symptoms of SZ and/or BD,
while at the same time targeting parasitism (Fond et al., 2015). Al-
though anti-psychotics showed inhibitory activity of parasite replica-
tion in vitro (Fond et al., 2014; Goodwin et al., 2011; Jones-Brando
et al., 2003), other studies failed to show any effects in vivo (Goodwin
et al., 2008; Saraei et al., 2015). A recent study by David et al. eval-
uated the efficacy of a ß-lactam antibiotic ceftriaxone, that rescues
extracellular glutamate concentrations on neuronal pathology and
function (David et al., 2016). Although ceftriaxone had a positive effect
on infection-induced glutamate dysregulation and was neuroprotective
in mice, it did not alter the immune response to the infection, neither
did it affect mouse behaviour. More recently, efforts to develop vac-
cines against infection has shown that Toxoplasma-expressed heat shock
protein 70 induces massive iNOS expression and reduces brain para-
sitism, pointing towards a possible protective therapy against the
parasite (Czarnewski et al., 2017). Nevertheless, effects of NO pro-
duction on behaviour remain to be determined, and further research is
required before any viable vaccine can be developed. Recently, a DNA
vaccine based on a recombinant eukaryotic plasmid was shown to offer
protective immunity in mice against the highly virulent RH strain (Chen
et al., 2017)
11. Conclusions and future perspectives
The current model of Toxoplasma-induced behavioural changes
posits that a complex interplay between changes in the brain as well as
immune activation leads to an overall deficit in cognitive and affective
function, manifesting as neuropsychiatric dysfunction in the infected
host. There may be changes in neuronal activity caused by the parasite
itself, an adaptation towards the inflammatory environment, and/or an
effect by the pro-inflammatory elements that cause collateral damage to
the neurons while the host actively fights the parasitism. Either way,
there is no magic bullet that can relieve the host of the parasite infec-
tion while at the same time preventing or reversing the neurological
damage already caused. Research in the fairly new field of neu-
roimmune communication has already produced some exciting data on
how the peripheral immune system can communicate with the CNS
using common molecular signalling cues, leading to dysregulation in
brain functions. However, in terms of specific mechanisms related to
Toxoplasma infection, our understanding still remains naive.
An important aspect of Toxoplasma infection is its ability to export
effector proteins into the host cells (Coffey et al., 2016; Hakimi et al.,
2017). What is still unknown is which proteins, if any, Toxoplasma
exports into the host neurons during the chronic stages and what are
their effects on the function and survival of those neurons.
Another way in which a links could be established between
Toxoplasma and changes in the structure and function of the brain is by
studying parasite clearance, or by not allowing chronic Toxoplasma
infection to be established in the brain. A recent study suggests that
upon infection with an attenuated Toxoplasma strain, mice still dis-
played changes in behaviour, suggesting that an ongoing (chronic) in-
fection may not be needed to alter the brain (Ingram et al., 2013).
Unfortunately, complete clearance of Toxoplasma cysts by drugs is not
yet possible, but a few mouse studies have tested compounds that lead
to a reduction in brain cysts (Alday and Doggett, 2017). This is an
avenue of continued research in the hopes that clearing brain cysts
might help alleviate mental illnesses. Furthermore, several parasite
mutants have become available that have reduced chronic infection or
84
Neuroscience and Biobehavioral Reviews 96 (2019) 72–92
that appear not to be able to persist (Fox et al., 2016; Uboldi et al.,
2015). Using these strains, as well as others that are conditionally at-
tenuated (Brown et al., 2017), in either growth or ability to export
proteins into the host neurons, may also help shed light on the role of
Toxoplasma in neuronal dysfunction.
In this context, it is important to note that current research into the
role of Toxoplasma in mental health is mostly associative, and solid
links between cause and effects have not been established. The next big
discoveries in this field would now focus on characterising specific
molecules that are responsible for the observed changes from both the
parasite and host side. In terms of developing a functional link between
Toxoplasma infection and human neuropsychiatric conditions then
clinically available drugs would need to be developed and trials per-
formed to see if treatment leads to improvements in conditions. This
may not show anything as the damage by Toxoplasma (direct or in-
directly through immune activation) may have already been enough to
yield ongoing brain dysfunction. Nevertheless, developing an under-
standing of the link between Toxoplasma and neuropsychiatric disease
is still important as it may provide impetus to develop vaccines to
prevent infection and thus alleviating one environmental factor that
could be causing problems of brain function.
Acknowledgements
We would like to thank members of the Tonkin Laboratory for
helpful discussions that has contributed towards the preparation of this
manuscript. The research in this laboratory is supported by The David
Winston Turner Foundation, Melbourne. AJH is an NHMRC Principal
Research Fellow.
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