Toxoplasma gondii is a parasite that infects around a third of the world's population. It can cause health issues in pregnant women and immunocompromised individuals. Some studies have found associations between T. gondii infection and changes in human behavior. This literature review will examine the parasite's ability to manipulate host behavior in rodents and humans, the potential mechanisms involved, and whether human manipulation could be adaptive for the parasite. It will also discuss diagnosis, treatment and prevention of toxoplasmosis.

1. Literature Review
2015/2016
(School of BiologicalSciences)
Toxoplasma gondii and The Host
Manipulation Hypothesis
– Are humans manipulated?
Phoebe Sutton
1302208
ProfessorRichard Wall

2. 1
Abstract
Toxoplasma gondii is a parasite of global importance, infecting around a third of the
world’s population. For those especially at risk, pregnant women and immune
compromised persons, effects manifest as congenital toxoplasmosis, retinochoroiditis, or
life-threatening encephalitis. Studies have shown Toxoplasma to have influences on
human behaviour, causing an increase in road accidents, homicides, suicides and mental
illnesses such as bipolar disorder and schizophrenia. The cause is controversial.
Toxoplasma can manipulate host behaviour to increase its own transmission, but as
humans are dead end hosts, the purpose of human manipulation is unclear. Instead,
behaviour changes are attributed to side-effects of parasite pathology. However,
research into mechanisms of host manipulation and a possible evolutionary link between
humans and Toxoplasma reveals that humans may indeed be purposefully manipulated.
This review will critically examine the manipulative abilities of Toxoplasma, as observed
in rodents and humans, and the mechanisms used. It will cover the question of adaptive
manipulation in humans, in relation to a curious evolutionary link, concluding with
diagnosis, treatment and prevention of toxoplasmosis and where future research could
take our understanding.
Introduction
Toxoplasma gondii, so named by its discoverers, was first observed in the tissues of
the North African rodent, Ctenodactylus gundi (Nicolle and Manceaux, 1908; 1909), and
has since inspired over 100 years of research.
Toxoplasma is contained within the phylum Apicomplexa, and the parasite subclass
coccidia (Frenkel et al., 1970). Unlike typical coccidia, Toxoplasma has been shown to
infect a remarkable range of hosts, including humans, felines, seven orders of non-feline
mammals, five orders of birds, and is even found within the marine environment
(Miller et al., 1972; Conrad et al., 2005).
Toxoplasma is an obligate intracellular protozoan parasite and follows an
apicomplexan lifecycle, through the predator-prey cycle of cats and birds, or small
mammals (Fig. 1). The sexual stage of the lifecycle is completed within the intestinal
tract of the definitive feline host and transmitted via a faecal–oral route. For ~2 weeks,
infected cats shed oocysts in the faeces that undergo sporogony between 2 – 5 days, in
Trophozoit
e
Merozoite
Gametozoites
Oocyst
Sporozoites
Figure 1. Upon infection of the intermediate host, sporozoites mature into free-form trophozoites
and proliferate with the host tissues through endodyogeny (Goldman et al., 1958). Merozoites are
produced and proliferated by mitotic merogony. Upon entry of the definitive host, gametocytes are
formed via gametogony. Fertilisation combines microgametes and macrogametes to create
zygotes that are released into the environment as oocysts. Oocysts then undergo sporogony into
infective sporozoites.
Made using information from Schmidt and Roberts (2009).
KEY
Merogony
 Gametogony
Fertilisation
Sporogony

3. 2
an aerobic environment below body temperature (Fig. 2a/b). Oocysts are non-infective
until after sporulation correlating with maximum infectivity in mice (Dubey et al., 1970).
The asexual cycle then occurs in the extraintestinal tissues of intermediate hosts upon
ingestion. In addition to domestic cats, bobcat, ocelot, jaguarundi, cougar, and Asian
leopard cats can shed oocysts (Jewell et al., 1972), leading researchers to believe
Toxoplasma originated as an intestinal parasite of Felidae.
‘Tachyzoite’ and ‘bradyzoite’ describe Toxoplasma trophozoites and merozoites,
respectively (Fig. 2c/d) (Frenkel, 1973). Tachyzoites are the fast developing stage of
Toxoplasma, present in acute infection (Schmidt and Roberts, 2009). They spread
around the body by hijacking immune cells such as plasmacytoid dendritic cells, and use
them as ‘Trojan horses’ to access organ tissues and invade the brain extravascular
space (Bierly et al., 2008). At chronic infection, bradyzoites are found grouped in tissue
cysts, located in muscles and immune-privileged sites of the body, including the brain,
eyes, testes, placenta and foetus (Hitziger et al., 2005). Cysts undergo periodic cycles of
rupture and encysting, causing re-emergence of the infection that is suppressed by the
immune system. This creates a condition called premunition, in which the pathogen
remains present in the body and protects the host from superinfection
(Schmidt and Roberts, 2009). Upon digestion, the cyst wall is dismantled by pepsin or
trypsin, however bradyzoites are resistant to digestion by gastric juices (pepsin – HCl)
(Jacobs et al., 1960). Cysts confer an evolutionary advantage to Toxoplasma, allowing
transmission through infected meat by carnivorism. Moreover, transplacental
transmission, from mother to foetus, has been found in humans (Wolf et al., 1939), sheep
(Hartley and Marshall, 1957), and rodents, persisting through five generations of mice
(Beverley, 1959).
However, the lifecycle is more complex than an obligatory two-host cycle (Fig. 3).
Oocysts and tachyzoites are also infective to cats, although, as seen in the prepatent
periods of these agents, transmission is most effective through bradyzoites
(Dubey et al., 1970). This oddity means the entire lifecycle can be completed in the
definitive feline host. Additionally, Toxoplasma is facultatively heteroxenous between
intermediate hosts (Frenkel et al., 1970), which suggests carnivorism among
intermediate hosts is another, possibly common, route of proliferation. Toxoplasma is
infective to nearly every warm-blooded animal, so it is no surprise that prevalence levels
are high across species (Table 1).
Seroprevalence of Toxoplasma, a measure of accumulated exposure over a
lifetime within specified social surroundings, has fallen in the human global population
from 42% (1986-1999) to 25-30% (Tenter et al., 2000; Pappas et al., 2009), dependent
on climate, socioeconomic parameters, and population habits in hygiene and diet
(Fig. 4). Humans acquire Toxoplasma congenitally or postnatally, through oocyst
exposure or from ingesting infected undercooked meat.
Figure 2. Images of (a) freshly shed oocyst, (b) a sporulated oocyst containing sporozoites,
(c) tachyzoites, and (d) cyst containing numerous bradyzoites.
Images from Dubey et al. (1970)

4. 3
Location of
study
Authors Cats (%) Rats (%) Birds (%)
Sea Otters
(%)
Panama City,
Panama
Frenkel et al.
(1995)
45.6 23.3 13.4 –
The
Netherlands
Opsteegh et al.
(2012)
18.2 – – –
Alabama
Lindsay et al.
(1993)
– – 26.7 –
Scotland
Jackson et al.
(1986)
–
(a) 20.0
(b) 17.6
(c) 10.9
– –
UK Farm
populations
Webster
(1994a)
– 35.0 – –
California
Conrad et al.
(2005)
– – – 38.0 – 52.0
Figure 3. Life cycle of Toxoplasma, showing faecal transmission, transplacental and
carnivorism, also included is the direct cycle within the feline host. Paratenic hosts, such as
earthworms, are transitionary hosts which the parasite can infect, but cannot undergo any
development (Bettiol, 2000).
Image from Webster (2001)
Table 1. Prevalence of Toxoplasma within host species around the world. Jackson et al. (1986)
recorded prevalence in (a) Apodemus sylvaticus, (b) Clethrionomys glareolus, and (c) Rattus
norvegicus.

5. 4
Carnivorous transmission was first demonstrated when comparing Toxoplasma
acquisition rates before (10%) and after adding barely cooked or lambs meat (100%) to
the diet of children (Desmonts et al., 1965). High prevalence in sheep (48.5%) is a
cause for concern, including transmission from rats, through pigs, and then to humans
(Weinman and Chandler, 1956; Shaapan et al., 2015). Indeed, 38% of meat products
sold in UK retail outlets are contaminated (Aspinall et al., 2002). Countries that eat raw
meat as ‘gourmet’, such as Europeans, have an increased risk of infection (Fig. 4).
High prevalence in the tropical South Americas (Fig. 4) is accounted to a large feral
cat population and persistence of oocysts in the environment, which can contaminate
fingers or food (Frenkel et al., 1970; Ruiz et al., 1973). Oocysts have been found to
remain infectious to mice for up to a year (Hutchison, 1965), persist in moist soil for at
least 4 months (Frenkel et al., 1970) and contaminate water sources
(de Moura et al., 2006). Continued exposure to soil increases prevalence, as seen in the
indigenous tribes of Brazil (57.3–78.8%) (Sobral et al., 2005).
Congenital toxoplasmosis is solely transmitted by primary infection of the mother
during pregnancy; the disease is most likely transmitted late in pregnancy (72% at 32
weeks) but greatest disease severity is from early infection (Dunn et al., 1999). If
infection does not result in miscarriage or stillbirth, clinical signs include hydrocephaly,
cerebral calcifications and retinochoroiditis (Koppe and Rothova, 1989). Mild cases can
be asymptomatic or manifest as visual and intellectual handicaps (Saxon et al., 1973).
Acquired toxoplasmosis is generally asymptomatic; however, toxoplasmic
retinochoroiditis can develop as lesions in or near the eyes (Silveira et al., 2001).
Immune deficient persons, for example chemotherapy and transplant patients, or those
with immune diseases such as acquired immunodeficiency syndrome (AIDs), usually
contract toxoplasmosis from reactivation of a previous chronic infection, resulting in
encephalitis (Luft and Remington, 1992). Economically, toxoplasmosis is estimated to
cost the United States $7.7 billion annually (Buzby and Roberts, 1996).
As a result of the intimate link between transmission and predation by cats,
Toxoplasma gondii has evolved the ability to manipulate intermediate host behaviour.
Despite being a dead-end host (Fig. 3), behavioural changes have been recorded in
Toxoplasma-positive humans. To determine the cause of these alterations, one must
examine the host manipulation hypothesis and the effect Toxoplasma infection has on
other hosts, such as rodents.
Figure 4. Global Toxoplasma seroprevalence. Dark red equals prevalence ≥60%, light red
equals 40–60%, yellow 20–40%, blue 10–20% and green equals prevalence <10%. White
equals absence of data.
Figure from Pappas et al. (2009).

6. 5
The Host Manipulation Hypothesis
The Host Manipulation Hypothesis presupposes that a parasite induces specific
alterations on host behaviour to increase its own transmission frequency, influencing only
the behaviours beneficial to transmission efficiency, and leaving global behaviours intact.
This is achieved genetically, creating an extended phenotype of the host; traits in one
organism (the host) are modified either directly or indirectly by genes in another organism
(the parasite) (Dawkins, 1982). This ability has evolved independently multiple times,
over various major parasite lineages, showing a strong adaptive advantage
(Moore, 2002).
Today, there are numerous examples of parasite manipulation of host behaviour,
morphology and/or physiology, ranging from slight modification to novel behaviours.
Poulin (2010) classified the diversity of parasite manipulation, each strategy negotiating a
transmission obstacle: (1) ‘Spacial displacement’, where the host moves out of the
habitat it typically resides, into a suitable habitat for the parasite to continue its lifecycle;
(2) ‘Manipulation of vectors’, where vector feeding behaviour is altered to increase
host visitations and therefore infections; (3) ‘Protection of the parasite’, where the
parasite pupae is protected from abiotic and biotic threats, by the production of
structures, physical defence or removing the pupae to a specific microhabitat;
(4) ‘Tropic transmission’, where the intermediate host is altered in colouration or
behaviour, increasing the risk of predation by the hosts’ natural predator in the lifecycle
– of which Toxoplasma gondii is a renowned example.
Following the rule of parsimony, several non-adaptive explanations have been
suggested: (1) ‘Side-effects’, where the observed changes in the host arise from the
pathology of the parasite or the defence response of the host immune system
(Minchella, 1985); (2) ‘By-products’, in which transmission is increased as a
consequence of infection but is not adaptive; for example, a parasitised host may have
increased energy requirements and coincidentally forages more, increasing risk of
predation (Poulin, 1995); (3) ‘Fortuitous payoffs of other adaptations’, for example,
ecysting in the central nervous system, although fundamentally selected for protection
against the host immune system, is also required for manipulating behaviour
(Moore and Gotelli, 1990).
If virulence is connected to transmission, it will become a target of natural selection,
and the same principle applies to parasite-induced behaviours. Even beneficial
side-effects can become adaptations through selection (Poulin, 2010), blurring the line
for researchers. Four criteria were outlined by Poulin (1995) to settle the adaptation
argument, and it was later established that the most credible evidence for demonstrating
a fitness benefit for the parasite, is establishing a genetic basis for increased
transmission or survival (Poulin, 2010), which for Toxoplasma is increased predation of
infected hosts.
Toxoplasma manipulation in Rodents
Behavioural manipulations have been best studied in rodents, natural trophic prey of
the domestic cat. Research has shown infected laboratory mice to have a diminished
learning capacity, working memory, motor coordination and balance (Witting, 1979).
Adaptively, the mouse is easier to catch, which enhances transmission. However, higher
brain cyst load is observed in mice during latent toxoplasmosis, compared to rats
(Berenreiterová et al., 2011; Vyas et al., 2007), leading to the conclusion that these
altered functions are side-effects of brain inflammation and disruption. This is supported
by the decreased learning ability of mice with increasing number of brain cysts
(Witting, 1979). For this reason, Hrdá et al. (2000) suggests the rat is a better model for
studying behavioural manipulations, as they have superior resistance to Toxoplasma.
Research found infected rodents are significantly more active (Mice: Hay et al. 1984;
Rats: Webster, 1994b). Webster (1994b) performed his study, as close as possible to
biological reality, on wild and laboratory rats (both Rattus norvegicus) and their hybrid
offspring, thereby accounting for varying degrees of generalised encephalitis; previous

7. 6
parasite loads; and inevitable subtle behavioural deviations in captive-bred rats.
Furthermore, to discount side-effects of parasite pathology, infections with a direct
lifecycles parasite (Syphacia muris) was compared and, as expected, no effect was seen
on activity levels (Webster, 1994b).
Moreover, afflicted rodents demonstrate decreased anxiety
(Mice: Takeda et al., 1998; Rats: Gonzalez et al., 2007) and neophobia
(Mice: Hay et al., 1984; Hutchison et al., 1980; Rats: Webster et al., 1994;
Berdoy et al., 1995), most significantly in rats, which are renowned for avoiding novel
stimuli (Barnett and Cowan, 1976). The reactions of wild Toxoplasma-infected rats to
novel food-related stimuli were found to be significantly less fearful compared to
base-line data, translating to an increased likelihood of capture in live traps. Again, a
similar effect was not seen in direct lifecycle parasitic infections (Webster et al., 1994).
More importantly, an interest in novel stimuli increases the attractiveness of an infected
rodent to a cat, whilst having no impact on other behaviours such as social status and
mating success (Berdoy et al., 1995) fulfilling the manipulation hypothesis criteria.
The most striking behavioural modification involves the complete reversal of innate
aversion to cat odour. Laboratory rodents, never before acquainted with a cat, will
demonstrate a strong aversive behaviour (Webster, 2001). However, when infected with
Toxoplasma, rodents not only show a lack of avoidance but a ‘suicidal’ preference,
termed The Fatal Attraction Phenomenon (Mice: Ingram et al., 2013;
Rats: Berdoy et al., 2000). Inexplicable by parasitosis, this effect is specific to feline
urine and ensures infected animals are less likely to be predated by non-definitive hosts
such as mink (Lamberton et al., 2008).
Finally, Toxoplasma has an effect on mate choice (Dass et al., 2011). Uninfected
female rats spent more time with infected males, and allowed them more mating
opportunities. Toxoplasma can be transferred via the sperm of infected male rats,
thereby increasing congenital transmission. However, caution should be taken, as this
was a small study, and results should be repeated (Dass et al., 2011).
Taken as a whole, the evidence for Toxoplasma gondii host manipulation is
convincing. However, the definitive demonstration of increased transmission through
predation rates of infected against non-infected rodents has yet to be undertaken
(Vyas, 2015). Nevertheless ‘by-products’ or ‘side-effects’, such as energy requirements
and neurodegeneration, cannot account for the consistent behavioural changes; none of
the stated studies found variations in foraging; likewise, direct lifecycle parasites showed
no comparative effects – therefore a proximate mechanism is required
(Vyas and Sapolsky, 2010).
Proximate Mechanisms for Host Modification
Parasites affect host phenotypes either directly or indirectly. Direct mechanisms
involve secretions from the parasite influencing changes in host neurons, nervous
system or muscles. Indirect mechanisms affect other aspects, for example immunity,
metabolism or host development (Thomas et al., 2005).
Cyst tropism to particular areas of the brain is thought to be a direct influence of
Toxoplasma. However, research shows limited targeted tropism, instead tending
towards a ‘probabilistic’ distribution. 92% of examined brain regions contained tissue
cysts; however, the cerebellum had a consistently low incidence, suggesting myelinated
bodies or greater cellular density act as a natural barrier (Berenreiterová et al., 2011).
Hematogeneous dissemination is suggested as a contributing factor in cyst infestation
(Dellacasa-Lindberg et al., 2007). However, no increase in cyst density was observed in
high metabolic regions such as the retrosplenial and auditory cortices, or subcortical
regions. Within the small sample, a slight increase in cyst number was seen in regions
associated with defensive or aversive behaviours, including the amydgala, hippocampus
and nucleus accumbens (Berenreiterová et al., 2011). These structures are located in
the limbic system, a primitive system of the mammalian brain, known to be involved in
emotion, self-preservation and procreation (Isaacson, 2003).

8. 7
Ingram et al. (2013) suggested that host behaviour change could be independent of
cysts or associated brain inflammation; instead, Toxoplasma could use ‘covert tropism’.
Effector proteins that manipulate cellular processes, are injected into brain cells prior to
parasite invasion (Saeij et al., 2007); however, in many cases, the brain cell is not
invaded. These “co-opted” cells can even outnumber infected cells (Koshy et al., 2012),
influencing the host without presence of the parasite itself.
An alternative to the tropic model is modulation of neurotransmitters associated with
mood, learning, memory and cerebral blood flow. Dopamine has a covert role in
motivation and goal-directed behaviours (Salamone and Correa, 2012); and
norepinephrine is a stress hormone, associated with the ‘fight or flight’ response;
abnormal rises result in anxiety disorders (Wang et al., 1999). Norepinephrine
decreased by 28% in acutely infected mice, whereas, dopamine increased by 14% in
chronically infected mice (Stibbs, 1985). A respective decrease and increase in these
molecules should produce an anxiolytic action, increasing exploratory behaviour and
decreasing neophobia, as seen in Toxoplasma infection.
Toxoplasma could increase dopamine directly. After mapping the parasite genome
in 2005 (Khan et al., 2005), Toxoplasma genes AAH1 and AAH2 were found to have
sequence similarity to a rate-limiting enzyme, tyrosine hydroxylase, in the dopamine
synthesis pathway (Gaskell et al., 2009). Theory follows that Toxoplasma creates an
extended phenotype by supplying the homologous enzyme, establishing a
hyperdopaminergic drive. Accordingly, high amounts of dopamine are found in cysts in
vivo and dopamine production of Toxoplasma-infected dopaminergic neurons increases
in vitro (Prandovszky et al., 2011). Rather than facilitating regional alterations of
dopamine, the AHH genes may be required for growth outside of non-dopaminergic cells,
and therefore non-adaptive for host manipulation (Wang et al., 2014). Intriguingly, drugs
that function as dopamine receptor antagonists reduce adverse behavioural traits of
infected rats and also have anti-parasitic properties, disrupting Toxoplasma replication in
vitro (Jones–Brando et al., 2003; Webster et al., 2006).
Furthermore, dopamine regulates aversive behaviours in the nucleus accumbens
(Wenzel et al., 2015). The structure is divided into the shell and the core subregions;
each receives dopaminergic inputs from different circuitry structures of the brain, and
integrates those motivations into action. Negative stimuli inhibit dopamine release in the
shell subregion, whilst enhancing dopamine release in the core; removal of the negative
stimuli correlates with a respective increase in the nucleus accumbens shell, and
decrease in the core (Wenzel et al., 2015). The shell influences emotional responses,
and is closely linked with the hippocampus and amygdala, regions to which Toxoplasma
shows mild tropism (Isaacson, 2003; Berenreiterová et al., 2011). Most compellingly,
Toxoplasma infection reduces dopamine in the nucleus accumbens core, without
affecting the shell, in what could be a mechanism for manipulation (Tan et al., 2015).
Hormone and epigenetic modification are implicated as a combined mechanism for
The Fatal Attraction Phenomenon, and further explain preferential mate choice in female
rats (Berdoy et al., 2000; Dass et al., 2011). Infestation of the immune-privileged testes
directly causes an upregulation of testosterone (androgen) production in the Leydig cells
(Lim et al., 2013), consequently increasing the amount of α2u-globulins, thereby making
infected males more attractive (Kulkarni et al., 1985; Vasudevan et al., 2015).
Testosterone is known to orchestrate sexual behaviours, and shown to reduce fear, in
rats as well as humans (King et al., 2005; Hermans et al., 2006). This method can
theoretically increase Toxoplasma transmission both sexually, through increased
horizontal and vertical spread in the prey species via mating, and trophically, by
decreasing vigilance to predatory risk. Conclusively, when castrated male rats were
infected, no behavioural effects on fear aversion were seen (Lim et al., 2013).
Moreover, testosterone binds to receptors found in the medial amygdala, a region
containing high numbers of arginine vasopressin (AVP) neurons. There are two separate
circuits within the medial amygdala: the posteroventral area (MePV), which is connected
to the olfactory system and activated in a response to cat odour (Dielenberg et al., 2001);
and the posterodorsal medial amygdala (MePD), which is activated upon exposure to
sexual pheromones (Goodson and Kabelik, 2009). AVP neurons are associated with
sexual responses, and activated during copulation in mice and other species

9. 8
(Ho et al., 2010). Increased testosterone reduces epigenetic methylation of the AVP
gene promoter, enhancing arginine vasopressin synthesis (Dass and Vyas, 2014).
During a normal response to cat odour, the MePV is preferentially activated over MePD;
however, in an infected rat, a greater number of sociosexual MeDP neurons are
activated (House et al., 2011), resulting in sexual attraction to feline urine. This
mechanism is thought to act on anxiolytic progesterone in females with the same result
(Golcu et al., 2014). However, this could be a ‘fortuitous payoff’ from infestation of the
testes and until mean trait values for parasitised and non-parasitised hosts have been
compared, adaptive manipulation by the methods above remains unproven.
The Fatal Attraction Phenomenon
The limbic system is highly conserved across vertebrates (Isaacson, 2003),
therefore the manipulations Toxoplasma exerts on this system in the Fatal Attraction
Phenomenon in rodents, should translate to olfactory function changes other
intermediate hosts, including humans (Klein, 2003). When asked to rate the intensity
and pleasantness of domestic cat, dog, hyena, tiger and horse urine, human males
strongly rated cat urine as more pleasant compared to non-infected males (p = 0.0025).
However, infected females rated the same odour as less pleasant. This gender
dependent trend was also non-significantly observed with hyena urine, a member of the
Feliformia suborder (Flegr et al., 2011). As a dead-end host, human manipulation would
hold no benefit for Toxoplasma transmission, but because Toxoplasma acts on primitive
regions of the brain, it is conceivable that behavioural alteration of ‘inappropriate’ hosts is
common, therefore non-adaptive.
However chimps, our closest relative and the only living primate predated by a feline,
upon infection demonstrate specific attraction to the urine of their natural predator, the
leopard, over lion or tiger (Poirotte et al., 2016). In the fossil record, leopard canine
punctures have been discovered in an australopithecine calotte (Brain, 1970); moreover,
gnawing patterns on the bones of Homo erectus found in Zhoukoudian, is accounted to
the Pleistocene hyaenid, Pachycrocuta brevirostris (Boaz et al., 2000). This reveals a
potential residual ancestral link between Toxoplasma, early hominids and predation by
Felidae (Hart and Sussman, 2005). As predation rates of infected, compared to
non-infected chimps cannot be experimentally performed on ethical grounds,
manipulation is not conclusively proven. However, if this evolutionary connection is
correct, it is inferable that attraction to feline urine seen in modern humans is a product of
adaptive manipulation.
Behavioural Changes in Humans
In addition to altering perception of cat urine, researchers gathered evidence of
Toxoplasma-infected humans suffering reduced reaction times with long-term
concentration – non-productive for Toxoplasma transmission in today’s human.
However, after only testing for three minutes, the result is inconclusive
(Havlicek et al., 2001).
Larger studies have found potential behavioural effects, with Toxoplasma infection
positively influencing personality factors A (warmth), G (conscientiousness), L (vigilance),
O (apprehension), and Q2 (self-reliance) as measured by Cartell’s questionnaire
(Flegr et al., 1996). It may be that such people are more vulnerable to Toxoplasma
infection; however, a positive correlation between personality changes and duration of
infection, in both men and women, suggests these changes are parasite-induced
(Felgr et al., 1996; 2000).
Toxoplasma-infected humans are more impulsive aggressive, 22% of 110 tested
subjects diagnosed with intermittent explosive disorder were Toxoplasma-positive.
(Coccaro et al., 2016). These behavioural shifts can be gender dependent, for example,
infected females have heightened aggression and males have increased impulsivity
(Cook et al., 2015). An explanation for gender discrepancies can be found in differential

10. 9
testosterone levels – increased in males, decreased in females (Flegr et al., 2008)
– or temporal differences in cytokine production (Roberts et al., 1995).
Furthermore, aggression and impulsivity are an endophenotypes for self-directed
violence. Indeed, toxoplasmosis is more likely in patients with general personality
disorders (Hinze-Selch et al., 2010); also bipolar disorder (Pearce et al., 2012) and
schizophrenia (Torrey et al., 2007). Moreover, unlike rodents, humans show a decrease
in novelty seeking (Flegr et al., 2003; Skallová et al., 2005), which is negatively
correlated with dopamine. The dopamine hypothesis of schizophrenia links psychosis to
increases in dopamine within the limbic system and amydgala (Willner, 1997).
The correlation between schizophrenia and Toxoplasma has been well established since
the 1950’s; a meta-analysis calculated toxoplasmosis increases the likelihood of
developing the condition by 2.73 (95% CI 2.10–3.60) (Torrey et al., 2007). Regarding
Toxoplasma transmission, schizophrenia causes social isolation, theoretically making
humans easier prey.
Increased toxoplasmosis prevalence against controls is recorded in subjects
hospitalised after a suicide attempt (41% vs 28% controls) (Yagmur et al., 2010).
Depressive symptoms could be caused by changes in tyrosine hydroxylase, resulting in a
decrease of norepinephrine, which at low levels results in decreased alertness and
depression (Leonard, 1997).
Unsurprisingly, Toxoplasma has received much media attention over the years
(McAuliffe, 2012), especially as those with latent toxoplasmosis have 2.65
(C.I. 95 = 1.76–4.01) times higher risk of a driving accident (Flegr et al., 2002); higher
incidence of seropositivity is found among prison inmates (21.1%) than controls (8.4%)
(Alvarado-Esquivel et al., 2014), and prevalence is even positively correlated with
national homicide rates (Lester, 2012).
Decreased goal-directed behaviours were found to be significant among the elderly
(Beste et al., 2014), but due to cumulative lifetime exposure, any effects of Toxoplasma
are expected to increase with age (Jones et al., 2001). Toxoplasma has been associated
with Alzheimer’s disease (Kusbeci et al., 2011), Parkinson’s disease
(Miman et al. 2010b), obsessive-compulsive disorder (Miman et al. 2010a) and cryptic
epilepsy (Yazar et al., 2003). However, many of these studies tested one association
with small (≤52) selected or clinical trials, and are therefore inconclusive as effects of
manipulation. Comprehensive studies, where many associations are examined within a
large representative group of non-institutionalised citizens, provide a clearer view of
Toxoplasma effects (Pearce et al., 2012; Sugden et al., 2016). Such studies only found
a significant relationship with bipolar disorder, suggesting that Toxoplasma behavioural
modifications could be less widespread, but still relevant to humanity.
What can be done?
People suffering the effects of Toxoplasma can be diagnosed and treated. The first
serological diagnostic tool, Sabin-Feldman dye test for Toxoplasma immunoglobulin G
(IgG) antibodies, is still used today to determine seroprevalence – a quantitative measure
of relative protection against infection within that population (Sabin and Feldman, 1948).
A standard measure anti-Toxoplasma sera was supplied by the World Health
Organisation (WHO) Collaborating Centre for Research and Reference on
Toxoplasmosis (est. 1974) to allow comparison between countries (Hui et al., 2000).
The Modified Agglutination Test (MAT) requires no special equipment or conjugates,
and is used extensively in livestock (Desmonts and Remington, 1980); and
Enzyme-linked Immunosorbent Assays (ELISAs) are commonly used in studies.
The MAT, ELISA and Indirect Fluorescent Antibody tests can be modified to detect
immunoglobulin M (IgM) (Hui et al., 2000). IgM cannot cross the placenta, therefore cord
blood or infant serum is used to screen for congenital toxoplasmosis, with 75% accuracy
(Remington et al., 1968). However, PCR amplification of Toxoplasma genes B1, P30 and
ribosomal RNA remains the most reliable method of diagnosis (Burg et al., 1989;
Johnson et al., 1993).

11. 10
Healthy people recover and live with toxoplasmosis without treatment. Infected
persons who are ill, immunosuppressed or pregnant, can be treated with the standard
therapy of sulphonamides and pyrimethamine (Eyles and Coleman, 1953).
Pyrimethamine acts on the tachyzoite form of the parasite by inhibiting the enzyme
dihydrofolate reductase (DHFR), which reduces tetrahydrofolic acid production, required
for DNA synthesis and nuclear division. Sulphonomides act synergistically to prevent
production of dihydrofolic acid, resulting in a blockage of the folate pathway. This has a
toxic effect unless taken with folinic acid, which protects the bone marrow from folate
deficiency (Aspen Pharmacare, 2014).
Spiramycin is nontoxic and given to pregnant women in the 1st
and early 2nd
term,
before switching to the standard treatment (Desmonts and Couvreur, 1974). Infants born
with congenital toxoplasmosis are treated with the standard therapy for a year, which
could reduce adverse mental development (Saxon et al., 1973). Immune compromised
patients receive the standard therapy until their immune system recovers; or lifelong for
AIDs patients (cdc.gov, 2016).
Prevention
To minimise exposure, people are advised to wash their hands regularly; wear
gloves when gardening to avoid oocyst contamination; cover outdoor sandboxes; avoid
eating raw meat and follow proper meat preparation (Frenkel, 1973), such as freezing
meat for several days, as oocysts can survive at 2 – 5C for 10 days in muscle tissue
(Weinman and Chandler, 1956), before thoroughly cooking (Boch, 1967). Cat-owners
can minimise risk by withholding raw meat, keeping cats indoors and disposing of faeces
quickly. These measures are especially relevant to pregnant women and those with HIV
(cdc.gov, 2016).
Vaccination targets include feline oocyst shedding, congenital transmission and cyst
development in commercial meat. Vaccination with live bradyzoites of T. gondii mutant
T-263 prevents 84% of cats from oocyst shedding (Frenkel et al., 1991) and feline
vaccination successfully reduced incidence of Toxoplasma in both pig and rodent
population of eight pig farms in the US (Mateus-Pinilla et al., 1999). The commercial
vaccination Toxovax©, live incomplete tachyzoites of strain S48, reduces congenital
transmission in sheep (Buxton and Innes, 1995).
No human vaccine is available due to risk of an iatrogenic infection from vaccinating
with live agents (Kur et al., 2014). However encouraging research shows decreased
congenital transmission in mice inoculated with tachyzoite antigen (STAg)
(Roberts et al., 1994). Whilst a DNA vaccine delivering another tachyzoite surface
antigen, SAG-1, protects mice from acquired toxoplasmosis, but doesn’t prevent
transplacental transmission (Couper et al., 2003). Activation of mucosal defences as the
natural interface for infection has drawn particular attention (Cong et al., 2005).
Future Research
Until treatment or vaccination can target chronic infection, Toxoplasma will never be
eradicated. Therefore, in addition to continued education on prevention, worldwide
prevalence of Toxoplasma must be established and monitored, so that those at greatest
risk can protect themselves from any symptoms of toxoplasmosis.
As predation rates cannot be determined for Toxoplasma-infected humans and feline
predators, the question of adaptive manipulation in humans for the benefit of
transmission will remain inconclusive. However, further exploration of the evolutionary
history, and the molecular mechanisms of sickness behaviour associated with
Toxoplasma, could clarify the relationship and even improve mental illness treatments.
Infectious viruses are thought to underlie common forms of mental illness
(Tomonaga, 2004), which can be extended to include Toxoplasma. One patient was
alleviated of depressive symptoms upon successful treatment of Toxoplasma
(Kar and Misra, 2004). Other potential options include anti-psychotic drugs
(dopamine antagonists), which have anti-parasitic effects against Toxoplasma

12. 11
(Jones–Brando et al., 2003); or blocking increases of testosterone by means other than
castration (Lim et al., 2013).
Parasitoproteomics is a promising tool that enables researchers to study host
genomes, and in some cases the parasite genome, in action whilst under manipulation.
This could offer insights into gene-protein interactions and future therapies of
‘manipulation’ symptoms in humans such as bipolar disorder and schizophrenia
(Biron et al., 2005). Accordingly, further research into Toxoplasma gondii and other
parasites of the central nervous system could produce greater medical understanding of
immune-neural connections in the brain, and improve lives worldwide.
Word count: 4,951

13. 12
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