1302208 - lit. rev

26
Literature Review 2015/2016 (School of Biological Sciences) Toxoplasma gondii and The Host Manipulation Hypothesis – Are humans manipulated? Phoebe Sutton 1302208 Professor Richard Wall

Upload: phoebe-sutton

Post on 06-Jan-2017

19 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: 1302208 - Lit. Rev

Literature Review

2015/2016

(School of Biological Sciences)

Toxoplasma gondii and The Host Manipulation Hypothesis– Are humans manipulated?

Phoebe Sutton

1302208

Professor Richard Wall

Page 2: 1302208 - Lit. Rev

AbstractToxoplasma 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.

IntroductionToxoplasma 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

KEYMerogony

Gametogony

Fertilisation

Sporogony

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).

ASEXUAL

SEXUAL

Sporozoites

Oocyst

Gametozoites

Merozoite

Trophozoite

1

Page 3: 1302208 - Lit. Rev

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)

a

dcb

2

Page 4: 1302208 - Lit. Rev

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

Carnivorous transmission was first demonstrated when comparing Toxoplasma acquisition rates before (10%) and after adding barely cooked or lambs meat (100%) to

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)

3

Page 5: 1302208 - Lit. Rev

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).

4

Page 6: 1302208 - Lit. Rev

The Host Manipulation HypothesisThe 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 RodentsBehavioural 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 parasite loads; and inevitable subtle behavioural deviations in captive-bred rats.

5

Page 7: 1302208 - Lit. Rev

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 ModificationParasites 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).

Ingram et al. (2013) suggested that host behaviour change could be independent of cysts or associated brain inflammation; instead, Toxoplasma could use ‘covert tropism’.

6

Page 8: 1302208 - Lit. Rev

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 (Ho et al., 2010). Increased testosterone reduces epigenetic methylation of the AVP gene promoter, enhancing arginine vasopressin synthesis (Dass and Vyas, 2014). During a

7

Page 9: 1302208 - Lit. Rev

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 HumansIn 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 testosterone levels – increased in males, decreased in females (Flegr et al., 2008) – or temporal differences in cytokine production (Roberts et al., 1995).

8

Page 10: 1302208 - Lit. Rev

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).

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).

9

Page 11: 1302208 - Lit. Rev

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).

PreventionTo 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 – 5C 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 ResearchUntil 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 (Jones–Brando et al., 2003); or blocking increases of testosterone by means other than castration (Lim et al., 2013).

10

Page 12: 1302208 - Lit. Rev

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

11

Page 13: 1302208 - Lit. Rev

ReferencesAlvarado-Esquivel, C., Hernandez-Tinoco, J., Sanchez-Anguiano, L. F., Ramos-Nevarez, A.,

Cerrillo-Soto, S. M., Saenz-Soto, L. and Liesenfeld, O. (2014) High seroprevalence of Toxoplasma gondii infection in inmates: A case control study in Durango City, Mexico. Eur. J. Microbiol. Immunol. (Bp). 4: 76–82

Aspen Pharmacare Australia Pty. Ltd. (2014) "PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Retrieved 11 March 2016.

Aspinall, T. V., Marlee, D., Hyde, J. E. and Sims, P. F. G. (2002) Prevalence of Toxoplasma gondii in commercial meat products as monitored by polymerase chain reaction—food for thought? Int. J. Epidemiol. 32: 1193–1199

Barnett, S. A. and Cowan, P. E. (1976) Activity, exploration, curiosity and fear: an ethological study. Interdiscip. Sci. Rev. 1: 43–62

Berdoy, M., Webster, J. and Macdonald, D. (1995) Parasite-altered behaviour: is the effect of Toxoplasma gondii on Rattus norvegicus specific? Parasitology. 111: 403–409

Berdoy, M., Webster, J. P. and Macdonald, D. W. (2000) Fatal attraction in Toxoplasma-infected rats: a case of parasite manipulation of its mammalian host. Proc. R. Soc. (Lond) B. 267: 1591–1594

Berenreiterová, M., Flegr, J., Kubena, A. A. and Nemec, P. (2011) The distribution of Toxoplasma gondii cysts in the brain of a mouse with latent toxoplasmosis: implications for the behavioral manipulation hypothesis. PLoS One. 6: e28925

Beste, C., Getzmann, S., Gajewski, P. D., Golka, K., and Falkenstein, M. (2014) Latent Toxoplasma gondii infection leads to deficits in goal-directed behavior in healthy elderly. Neurobiol. Aging. 35: 1037–1044

Bettiol, S. S., Obendorf, D. L., Nowarkowski, M., Milstein, T. and Goldsmid, J. M. (2000) Earthworms as Paratenic hosts of toxoplasmosis in Eastern Barred Bandicoots in Tasmania. J. Wild. Dis. 36: 145–14

Beverley, J. K. A. (1959) Congenital transmission of toxoplasmosis through successive generations of mice. Nature. 183: 1348–1349

Bierly, A. L., Shufesky, W. J., Sukhumavasi, W., Morelli, A. E. and Denkers, E. Y. (2008) Dendritic cells expressing plasmacytoid marker PDCA-1 are Trojan horses during Toxoplasma gondii infection. J. Immunol. (Baltimore, Md: 1950). 181: 8485–8491

Biron, D. G., Moura, H., Marché, L., Hughes, A. L. and Thomas, F. (2005) Towards a new conceptual approach to "parasitoproteomics". Trends Parasitol. 21: 162–168

Boaz, N. T., Ciochon, R. L., Qinqi, X. and Jinyi, L. (2000) Large mammalian carnivores as a taphonomic factor in the bone accumulation at Zhoukoudian. Acta Anthropologica Sinica. 19: 224–234

Boch, J. (1967) Toxoplasma infection in domestic animals and their importance in food hygiene. Fleishwirtschaft. 47: 969–973

Brain, C. K. (1970) New finds at the Swartkrans australopithecine site. Nature. 225: 1112–1119Burg, J. L., Grover, C. M., Pouletty, P. and Boothroyd, J. C. (1989) Direct and sensitive detection

of a pathogenic protozoan, Toxoplasma gondii, by polymerase chain-reaction. J. Clin. Microbiol. 27: 1787–1792

Buxton, D. and Innes, E. A. (1995) A commercial vaccine for ovine toxoplasmosis. Parasitology. 110: S11–S16

Buzby, J. C. and Roberts, T. (1996) ERS updates US foodborne disease costs for seven pathogens. Food Rev. 19: 20–25

cdc.gov (2016) “You Can Prevent Toxo: A Guide For People with HIV Infection” Available from: http://www.cdc.gov/parasites/toxoplasmosis/

Coccaro, E. F., Royce Lee, R., Groer, M. W., Can, A., Coussons-Read, M. and Postolache, T. T. (2016) Toxoplasma gondii Infection: Relationship With Aggression in Psychiatric Subjects. J. Clin. Psychiatry. 77: 334–341

Cong, H., Gu, Q. M., Jiang, Y., He, S. Y., Zhou, H. Y., Yang, T. T., Li, Y. and Zhao, Q. L. (2005) Oral immunization with a live recombinant attenuated Salmonella typhimurium protects mice against Toxoplasma gondii. Parasite Immunol. 27: 29–35

Conrad, P. A., Miller, M. A., Kreuder, C., James, E. R., Mazet, J., Dabritz, H., Jessup, D. A., Gulland, F. and Grigg, M. E. (2005) Transmission of Toxoplasma: clues from the study of sea otters as sentinels of Toxoplasma gondii flow into the marine environment. Int. J. Parasitol. 35: 1155–1168

Cook, T., Brenner. L. A., Cloninger, C. R. et al. (2015) “Latent” infection with Toxoplasma gondii: Association with trait aggression and impulsivity in healthy adults. J. Psychiat. Res. 60: 87–94

12

Page 14: 1302208 - Lit. Rev

Couper, K. N., Nielsen, H. V., Petersen, E., Roberts, F., Roberts, C. W. and Alexander, J. (2003) DNA vaccination with the immunodominant tachyzoite surface antigen (SAG-1) protects against adult acquired Toxoplasma gondii infection but does not prevent maternofoetal transmission. Vaccine. 21: 2813–2820

Dass, S. A. H., Vasudevan, A., Dutta, D., Soh, L. J. T., Sapolsky, R. M. and Vyas, A. (2011) Protozoan parasite Toxoplasma gondii manipulates mate choice in rats by enhancing attractiveness of males. PLoS ONE. 6: e27229

Dass, S. A. H. and Vyas, A. (2014) Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala. Mol. Ecol. 23: 6114–6122

Dawkins, R. (1982) The Extended Phenotype. Oxford University Press, Oxford.de Moura, L., Bahia-Oliveira, L. M. G., Wada, M. Y., Jones, J. L., Tuboi, S. H., Carmo, E. H.,

Ramalho, W. M., Camargo, N. J., Trevisan, R., Graca, R. M. T., da Silva, A. J., Moura, I., Dubey, J. P. and Garrett, D. O. (2006) Waterborne outbreak of toxoplasmosis, Brazil, from field to gene. Emer. Infect. Dis. 12: 326–329

Dellacasa-Lindberg, I., Hitziger, N. and Barragan, A. (2007) Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging. Microbes Infect. 9: 1291–1298

Desmonts, G., Couvreur, J., Alison, F., Baudelot, J., Gerbeaux, J. and Lelong, M. (1965) Étude épidémiologique sur la toxoplasmose: de l’influence de la cuisson des viandes de boucherie sur la fréquence de l’infection humaine. Rev. Fr. Études Clin. Biol. 10: 952–958

Desmonts, G. and Couvreur, J. (1974) Toxoplasmosis in pregnancy and its transmission to the fetus. Bull. N.Y. Acad. Med. 50: 146–159

Desmonts, G. and Remington, J. S. (1980) Direct agglutination test for diagnosis of Toxoplasma infection: method for increasing sensitivity and specificity. J. Clin. Microbiol. 11: 562–568

Dielenberg, R. A., Hunt, G. E. and McGregor, I. S. (2001) “When a rat smells a cat”: the distribution of Fos immunoreactivity in rat brain following exposure to a predatory odor. Neuroscience. 104: 1085–1097

Dubey, J. P., Miller, N. L., and Frenkel, J. K. (1970) The Toxoplasma gondii oocyst from cat feces. J. Exp. Med. 132: 636–662

Dunn, D., Wallon, M., Peyron, F., et al. (1999) Mother-to-child transmission of toxoplasmosis: Risk estimates for clinical counselling. Lancet. 353: 1829–1833

Eyles, D. E. and Coleman, N. (1953) Synergistic effect of sulfadiazine and daraprim against experimental toxoplasmosis in the mouse. Antibiot. Chemother. 3: 483–490

Flegr, J., Zitkova, S., Kodym, P. and Frynta, D. (1996) Induction of changes in human behaviour by the parasitic protozoan Toxoplasma gondii. Parasitology. 113: 49–54

Flegr, J., Kodym, P. and Tolarova, V. (2000) Correlation of duration of latent Toxoplasma gondii infection with personality changes in women. Biological Psychology. 53: 57–68

Flegr, J., Havlicek, J., Kodym, P., Maly, M. and Smahel, Z. (2002) Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study. BMC Infect. Dis. 2: 11

Flegr, J., Preiss, M., Klose, J., Havlicek, J., Vitakova, M., and Kodym, P. (2003) Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii. Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol. Psychol. 63: 253–268

Flegr, J. Lindová, J. and Kodym, P. (2008) Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology. 135: 427–431

Flegr, J., Lenochová, P., Hodný, Z. and Vondrová, M. (2011) Fatal Attraction Phenomenon in humans – cat odour attractiveness increased for Toxoplasma-infected men while decreased for infected women. PLoS Negl. Trop. Dis. 5: e1389

Frenkel, J. K. (1973) Toxoplasma in and around us. BioScience. 23: 343–352Frenkel, J. K., Dubey, J. P., and Miller, N. L. (1970) Toxoplasma gondii: fecal stages identified as

coccidian oocysts. Science. 167: 893-896Frenkel, J. K., Pfefferkorn, E. R., Smith, D. D. and Fishback, J. L. (1991) Prospective vaccine

prepared from a new mutant of Toxoplasma gondii for use in cats. Am. J. Vet. Res. 52: 759–763

Frenkel, J. K., Hassanein, K. M., Hassanein, R. S., Brown, E., Thulliez, P. and Quinteronunez, R. (1995) Transmission of Toxoplasma gondii in Panama-City, Panama. Am. J. Trop. Med. Hyg. 53: 458–468

Gaskell, E. A., Smith, J. E., Pinney, J. W., Westhead, D. R. and McConkey, G. A. (2009) A unique dual activity amino acid hydroxylase in Toxoplasma gondii. PLoS One. 4: e4801

Golcu, D., Gebre, R. Z. and Sapolsky, R. M. (2014) Toxoplasma gondii influences aversive behaviors of female rats in an estrus cycle dependent manner. Physiol. Behav. 135: 98–103

13

Page 15: 1302208 - Lit. Rev

Goldman, M., Carver, R. K. and Sulzer, A. J. (1958) Reproduction of Toxoplasma gondii by internal budding. J. Parasitol. 44: 161–171

Gonzalez, L. E., Rojnik, B., Urrea, F., Urdaneta, H., Petrosino, P., Colasante, C., Pino, S. and Hernandez, L. (2007) Toxoplasma gondii infection lower anxiety as measured in the plus-maze and social interaction tests in rats: A behavioral analysis. Behav. Brain. Res. 177: 70–79

Goodson, J. L. and Kabelik, D. (2009) Dynamic limbic networks and social diversity in vertebrates: from neural context to neuromodulatory patterning. Front. Neuroendocrin. 30: 429–441

Hart, D. and Sussman, R. W. (2005). Man the hunted: primates, predators, and human evolution. New York [N.Y.]: Westview Press.

Hartley, W. J. and Marshall, S. C. (1957) Toxoplasmosis as a cause of ovine perinatal mortality. N.Z. Vet. J. 5: 119–124

Havlicek J., Gasova Z. G., Smith A. P., Zvara K., and Flegr J. (2001) Decrease of psychomotor performance in subjects with latent 'asymptomatic' toxoplasmosis. Parasitology. 122: 515–520

Hay, J., Aitken, P. P., Hair, D. M., Hutchison, W. M. and Graham, D. I. (1984) The effect of congenital Toxoplasma infection on mouse activity and relative preference for exposed areas over a series of trials. Ann. Trop. Med. Parasitol. 78: 611–618

Hermans, E. J., Putman, P., Baas, J. M., Koppeschaar, H. P. and van Honk, J. (2006) A single administration of testosterone reduces fear-potentiated startle in humans. Biol. Psychiat. 59: 872–874

Hinze-Selch, D., Daubener, W., Erdag, S. and Wilms S. (2010) The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients. Folia Parasitol (Praha). 57: 129–135

Hitziger, N., Dellacasa, I., Albiger, B. and Barragan, A. (2005) Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin-1 receptor signaling for host resistance assessed by in vivo bioluminescence imaging. Cell. Microbiol. 7: 837–848

Ho, J. M., Murray, J. H., Demas, G. E. and Goodson, J. L. (2010) Vasopressin cell groups exhibit strongly divergent responses to copulation and male–male interactions in mice. Horm. Behav. 58: 368–377

House, P. K., Vyas, A. and Sapolsky, R. (2011) Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii infected rats. PLoS ONE. 6: e23277

Hrdá, S., Votypka, J., Kodym, P. and Flegr, J. (2000) Transient nature of Toxoplasma gondii-induced behavioral changes in mice. J. Parasitol. 86: 657–663

Hui, Y. H., Sattar, S. A. and Nip, W.–K. (2000) Foodborne Disease Handbook, Second Edition: Volume 2: Viruses: Parasites: Pathogens, and HACCP. CRC Press. 390–405

Hutchison, W. M. (1965) Experimental transmission of Toxoplasma gondii. Nature. 206: 961–962Hutchison, W. M., Aitken, P. P. and Wells, B. W. P. (1980) Chronic Toxoplasma infections and

familiarity-novelty discrimination in the mouse. Ann. Trop. Med. Parasitol. 74: 145–150Ingram, W. M., Goodrich, L. M., Robey, E. A., and Eisen, M. B. (2013) Mice infected with low-

virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance. PLoS One, 8: e75246

Isaacson, R. L. (2003) Limbic System. eLS. 1–4 Jackson, M. H., Hutchison, W. M. and Siim, C. J. (1986) Toxoplasmosis in a wild rodent population

of central Scotland and a possible explanation of the mode of transmission. J. Zool. 209: 549–557

Jacobs, L., Remington, J. S., and Melton, M. L. (1960) The resistance of the encysted form of Toxoplasma gondii. J. Parasit. 46: 11–21

Jewell, M. L., Frenkel, J. K., Johnson, K. M., Reed, V. and Ruiz A. (1972) Development of Toxoplasma oocysts in neotropical Felidae. Am. J. Trop. Med. Hyg. 21: 512-517

Johnson, J. D., Butcher, P. D., Savva, D. and Holliman, R. E. (1993) Application of the polymerase chain reaction to the diagnosis of human toxoplasmosis, J. Infect. 26: 147–158

Jones, J. L., Kruszon-Moran, D., Wilson, M., McQuillan, G., Navin, T. and McAuley, J. B. (2001) Toxoplasma gondii infection in the United States: seroprevalence and risk factors. Am. J. Epidemiol. 154: 357–365

Jones–Brando, L., Torrey, F. and Yolken, R. (2003) Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr. Res. 62: 237–244

Kar N. and Misra B. (2004) Toxoplasma seropositivity and depression: a case report. BMC Psychiatry. 4: 1

14

Page 16: 1302208 - Lit. Rev

Khan, A., Taylor, S., Su, C., Mackey, A. J., Boyle, J., Glover, R. D., Tang, K., Paulsen, I. T., Berriman, M., Boothrooyd, J. C., Pfefferkorn, E. R., Dubey, J. P., Ajioka, J. W., Roos, D. S., Wootton, J. C. and Sibley, L. D. (2005) Composite genome map and recombination parameters derived from three archetypal lineages of Toxoplasma gondii. Nucleic. Acids. Res. 33: 2980–2992

King, J. A., De Oliveira, W. L. and Patel, N. (2005) Deficits in testosterone facilitate enhanced fear response. Psychoneuroendocrino. 30: 333–340

Klein, S. L. (2003) Parasite manipulation of the proximate mechanisms that mediate social behavior in vertebrates. Physiol. Behav. 79: 441–449

Koppe, J. G. and Rothova, A. (1989) Congenital toxoplasmosis: A long-term follow-up of 20 years. Int. Ophthalmol. 13: 387–390

Koshy, A. A., Dietrich, H. K., Christian, D. A., Melehani, J. H., Shastri, A. J., Hunter, C. A. and Boothroyd, J. C. (2012) Toxoplasma co-opts host cells it does not invade. PLoS Pathogens. 8: e1002825

Kulkarni, A. B., Gubits, R. M. and Feigelson, P. (1985) Developmental and hormonal regulation of α2u-globulin gene transcription. Proc. Natl. Acad. Sci. U.S.A. 82: 2579–2582

Kur, J., Holec-Gąsiorb, L. and Hiszczyńska-Sawickac, E. (2014) Current status of toxoplasmosis vaccine development. Expert Rev. Vaccines. 8: 791–808

Kusbeci, O. Y., Miman, O., Yaman, M., Aktepe, O. C. and Yazar, S. (2011) Could Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis. Assoc. Disord. 25: 1–3

Lamberton, P. H. L., Donnelly, C. A. and Webster, J. P. (2008) Specificity of the Toxoplasma gondii-altered behaviour to definitive versus non-definitive host predation risk. Parasitology. 135: 1143–1150

Leonard, B. E. (1997) The role of noradrenaline in depression: A review. J Psychopharmacol. 11: S39–S47

Lester, D. (2012) Toxoplasma gondii and homicide. Psychol. Rep. 111: 196–197Lim, A., Kumar, V., Dass, S. A. H. and Vyas, A. (2013) Toxoplasma gondii infection enhances

testicular steroidogenesis in rats. Mol. Ecol. 22: 102–110Lindsay, D. S., Smith, P. C., Hoerr, F. J. and Blagburn, B. L. (1993) Prevalence of encysted

Toxoplasma gondii in raptors from Alabama. J. Parasitol. 79: 870–873Luft, B. J. and Remington, J. S. (1992) Toxoplasmic encephalitis in AIDs. Clin. Infect. Dis.

15: 211–222Mateus-Pinilla, N. E., Dubey, J. P., Choromanski, L. and Weigel, R. M. (1999) A field trial of the

effectiveness of a feline Toxoplasma gondii vaccine in reducing T. gondii exposure for swine. J. Parasitol. 85: 855–860

McAuliffe, K. (2012) How your cat is making you crazy. In: The Atlantic, Quartz. Available from: http://www.theatlantic.com/magazine/archive/2012/03/how-your-cat-is-making-you-crazy/308873/

Miller, N. L., Frenkel, J. K. and Dubey, J. P. (1972) Oral infections with Toxoplasma cysts and oocysts in felines, other mammals, and in birds. J. Parasit. 58: 928–937

Miman, O., Mutlu, E. A., Ozcan, O., Atambay, M., Karlidag, R. and Unal, S. (2010a) Is there any role of Toxoplasma gondii in the etiology of obsessive–compulsive disorder? Psychiatry Res. 177: 263–265

Miman, O. Kusbeci, O. Y., Aktepea, O. C. and Cetinkaya, Z. (2010b) The probable relation between Toxoplasma gondii and Parkinson's disease. Neurosci. Lett. 475: 129–131

Minchella, D. J. (1985) Host life-history variation in response to parasitism. Parasitology. 90: 205–216

Moore, J. (2002) Parasites and the behaviour of animals. In: Oxford Series in Ecology and Evolution. Oxford University Press, USA.

Moore, J. and Gotelli, N. J. (1990) A phylogenetic perspective on the evolution of altered host behaviours: a critical look at the manipulation hypothesis. In: Barnard, C.J., Behnke, J.M. (Eds.), Parasitism and Host Behaviour. Taylor and Francis, London, 193–233

Nicolle, C. and Manceaux, L. (1908) Sur une infection à corps de Leishman (ou organismes voisins) du gondi. C. R. Seances Acad. Sci. 147: 763–766

Nicolle, C. and Manceaux, L. (1909) Sur un protozoaire nouveau du gondi. C. R. Seances Acad. Sci. 148: 369–372

Opsteegh, M., Haveman, R., Swart, A. N., Mensink-Beerepoot, M. E., Hofhuis, A., Langelaar, M. F. and van der Giessen, J. W. (2012) Seroprevalence and risk factors for Toxoplasma gondii infection in domestic cats in The Netherlands. Prev Vet Med. 104: 317–326

Pappas, G., Roussos, N. and Falagas, M. E. (2009). Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int. J. Parasitol. 39: 1385–1394

15

Page 17: 1302208 - Lit. Rev

Pearce, B. D., Kruszon-Moran, D. and Jones, J. L. (2012) The relationship between Toxoplasma gondii infection and mood disorders in the third National Health and Nutrition Survey. Biol. Psychiatry. 72: 290–295

Poirotte, C., Kappeler, P. M., Ngoubangoye, B., Bourgeois, S., Moussodji, M. and Charpentier, M. J. E. (2016) Morbid attraction to leopard urine in Toxoplasma-infected chimpanzees. Curr. Biol. 26: pR98–R99

Poulin, R. (1995) “Adaptive” change in the behaviour of parasitized animals: a critical review. Int. J. Parasitol. 25: 1371–1383

Poulin, R. (2010) Parasite manipulation of host behavior: an update and frequently asked questions. In: Advances in the study of behaviour, Academic Press, Burlington, MA. H.J. Brockmann (Ed.) 151–186

Prandovszky, E., Gaskell, E., Martin, H., Dubey, J., Webster, J. P., McConkey, G. A. (2011) The neurotropic parasite Toxoplasma gondii increases dopamine metabolism. PLoS ONE 6: e23866

Remington, J. S., Miller, M. J. and Brownlee, I. E. (1968) IgM antibodies in acute toxoplasmosis. II. Prevalence and significance in acquired cases. J. Lab. Clin. Med. 71: 855–866

Roberts, C. W., Brewer, J. M. and Alexander, J. (1994) Congenital toxoplasmosis in the Balb/c mouse: prevention of vertical disease transmission and fetal death by vaccination. Vaccine. 12: 1389-1394

Roberts, C. W., Cruickshank, S. M. and Alexander, J. (1995) Sex-determined resistance to Toxoplasma gondii is associated with temporal differences in cytokine production. Infect. Immun. 63: 2549–2555

Ruiz, A., Frenkel, J. K. and Cerdas, L. (1973) Isolation of Toxoplasma from soil. J. Parasit. 59: 204–206

Sabin, A. B. and Feldman, H. A. (1948) Dyes as microchemical indicators of a new immunity phenomenon affecting a protozoon parasite (Toxoplasma). Science. 108: 660–663

Saeij, J. P. J., Coller, S., Boyle, J. P., Jerome, M. E., White, M. W. and Boothroyd, J. C. (2007) Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature. 445: 324–327

Salamone, J. D. and Correa, M. (2012) The mysterious motivational functions of mesolimbic dopamine. Neuron. 76: 470–485

Saxon, S. A., Knight, W., Reynolds, D. W., Stagno, S. and Alford, C. A. (1973) Intellectual deficits in children born with subclinical congenital toxoplasmosis: a preliminary report. J. Pediatr. 72: 792–797

Schmidt, G. D. and Roberts L. S. (2009) Phylum Apicomplexa: Gregarines, Coccidia, and Related Organisms. In: Roberts L.S. and Janvoy, Jr, J. Foundations of Parasitology. 8th ed. New York: McGraw-Hill. 134–139

Shaapan, R. M., Kandil, O. M. and Nassar, S. A. (2015) Comparison of PCR and serologic survey for diagnosis of toxoplasmosis in sheep. Res. J. Parasitol. 10: 66–72

Silveira, C., Belfort Jr., R., Muccioli, C., Abreu, M. T., Martins, M. C., Victora, C., Nussenblatt, R. B. and Holland, G. N. (2001) A follow-up study of Toxoplasma gondii infection in southern Brazil. Am. J. Ophthalmol. 131: 351–354

Skallová, A., Novotná, M., Kolbeková, P., Gašová, Z., Veselý, V., Sechovská, M. and Flegr, J. (2005) Decreased level of novelty seeking in blood donors infected with Toxoplasma. Neuro Endocrinol Lett, 26: 480–486

Sobral, C. A., Amendoeira, M. R., Teva, A., Patel, B. N. and Klein, C. H. (2005) Seroprevalence of infection with Toxoplasma gondii in indigenous Brazilian populations. Am. J. Trop. Med. Hyg. 72: 37–41

Stibbs, H. H. (1985) Changes in the brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice. Ann. Trop. Med. Parasitol. 79: 153–157

Sugden, K., Moffitt, T. E., Pinto, L., Poulton, R., Williams, B. S. and Caspi, A. (2016) Is Toxoplasma gondii infection related to brain and behavior impairments in humans? Evidence from a population-representative birth cohort. PLoS One. 11: e0148435

Takeda, H., Tsuji, M. and Matsumiya, T. (1998) Changes in head-dipping behavior in the hole-board test reflect the anxiogenic and/or anxiolytic state in mice. Eur. J. Pharmacol. 350: 21–29

Tan, D., Soh, L. J. T., Lim, L. W., Daniel, T. C. W., Zhang, X. and Vyas, A. (2015) Infection of male rats with Toxoplasma gondii results in enhanced delay aversion and neural changes in the nucleus accumbens core. Proc. R. Soc. B. 282: 20150042

Tenter, A. M., Heckeroth, A. R. and Weiss, L. M. (2000) Toxoplasma gondii: From animals to humans. Int. J. Parasitol. 30: 1217–1358

16

Page 18: 1302208 - Lit. Rev

Thomas, F., Adamo, S. and Moore, J. (2005) Parasitic manipulation: where are we and where should we go? Behav. Processes. 68: 185–199

Tomonaga, K. (2004) Virus-induced neurobehavioural disorders: mechanisms and implications. Trends Mol. Med. 10: 71–77

Torrey, E. F., Bartko, J. J., Lun, Z.–R. and Yolken, R. H. (2007). Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophrenia Bull. 33: 729–736

Vasudevan, A., Kumar, V., Chiang, Y. N., Yew, J. Y., Cheemadan, S. and Vyas, A . (2015) α2u-globulins mediate manipulation of host attractiveness in Toxoplasma gondii–Rattus novergicus association. ISME J. 9: 2112–2115

Vyas, A., Kim, S. K., Giacomini, N., Boothroyd, J. C. and Sapolsky, R. M. (2007) Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc. Natl. Acad. Sci. U.S.A. 104: 6442–6447

Vyas, A. and Sapolsky, R. (2010) Manipulation of host behaviour by Toxoplasma gondii: what is the minimum a proposed proximate mechanism should explain? Folia. Parasitol. (Praha) 57: 88–94

Vyas, A. (2015) Mechanisms of host behavioral change in Toxoplasma gondii rodent association. PLoS Pathogens. 11: e1004935

Wang, Y.–M., Xua, F., Gainetdinova, R. R. and Carona, M. C. (1999) Genetic approaches to studying norepinephrine function: knockout of the mouse norepinephrine transporter gene. Biol. Psychiatr. 46: 1124–1130

Wang, Z. T., Harmon, S., O'Malley, K. L. and Sibley, L.D. (2014) Reassessment of the role of aromatic amino acid hydroxylases and the effect of infection by Toxoplasma gondii on host dopamine levels. Infect. Immun. 83: 1039–1047

Webster, J. P. (1994a) Prevalence and transmission of Toxoplasma gondii in wild brown rats, Rattus norvegicus, Parasitology. 108: 407–411

Webster, J. P. (1994b) The effect of Toxoplasma gondii and other parasites on activity levels in wild and hybrid Rattus norvegicus. Parasitology. 109: 583–589

Webster, J. P. (2001) Rats, cats, people and parasites: The impact of latent toxoplasmosis on behaviour. Microbes Infect. 12: 1037–1045

Webster, J. P., Brunton, C. F. A. and Macdonald, D. W. (1994) Effect of Toxoplasma gondii upon neophobic behaviour in wild brown rats, Rattus norvegicus. Parasitology. 109: 37–43

Webster, J. P., Lamberton, P. H., Donnelly, C. A. and Torrey, E. F. (2006) Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii’s ability to alter host behaviour. Proc. Biol. Sci. 273: 1023–1030

Weinman, D. and Chandler, A.H. (1956) Toxoplasmosis in man and swine - an investigation of the possible relationship. J.A.M.A. 161: 229–232

Wenzel, J. M., Rauscher, N. A., Cheer, J. F. and Oleson, E. B. (2015) A role for phasic dopamine release within the nucleus accumbens in encoding aversion: a review of the neurochemical literature. ACS Chem. Neurosci. 6: 16–26

Willner, P. (1997) The dopamine hypothesis of schizophrenia: current status, future prospects. Int. Clin. Psychopharmacol. 12: 297–308

Witting, P. A. (1979) Learning capacity and memory of normal and Toxoplasma-infected laboratory rats and mice. Zeit. Parasit. 61: 29–51

Wolf, A., Cowen, D. and Paige, B. (1939) Human toxoplasmosis: occurrence in infants as encephalomyelitis verification by transmission to animals. Science. 89: 226–227

Yagmur, F., Yazar, S., Temelb, H. O. and Cavusogluc, M. (2010) May Toxoplasma gondii increase suicide attempt – preliminary results in Turkish subjects? Forensic Sci. Int. 199: 15–17

Yazar, S., Arman, F., Yalçin, S., Demirtaş, F., Yaman, O. and Şahin, I. (2003) Investigation of probable relationship between Toxoplasma gondii and cryptogenic epilepsy. Seiz. Eur. J. Epil. 12: 107–109

17