**2. Effect of toxoplasma on different hosts**

#### **2.1 Cats as the definitive hosts of toxoplasma**

*Toxoplasma* has an indirect life cycle. This means that cats are the only host where *Toxoplasma gondii* can complete its reproduction cycle in which *T. gondii* undergoes full gametogenesis and mating in the feline intestine. This results in the generation of oocytes that are shed by cats [1, 2]. Several species of rodents, small birds, and warmblooded animals including, humans, dogs, rabbits, mice, rats, wild birds, and sea otters, for example, can ingest the oocytes. When this occurs, the parasite undergoes asexual reproduction and the oocytes can contaminate several different environments. The distribution of oocytes in the environment can lead to further infection by other hosts, with hopes of eventually returning to the feline species. Since the reproduction life cycle of *T. gondii* can only be completed in cats, T. gondii has developed strong selective pressures to evolve mechanisms that enhance transmission from the intermediate host to the definitive cat host. These mechanisms involve altering animal behavior, activity, personality, and cognition. The modification of the host's behavior is known as the "manipulation hypothesis" [2].

#### **2.2 Effect of toxoplasma on infected mice and rats**

Early studies looking at behavioral changes in rodents noted a decreased learning capacity and impaired memory. Piekarski et al. performed maze experiments with rats and mice who were infected with *Toxoplasma.* The authors noted that the learning performance of rats and especially mice were impacted and that the memory of mice and their overall activity was decreased. These were some of the initial observations that highlighted the influence of parasitic infections on [2]the behavior of hosts [3].

Cats are immediately attracted to moving and exposed objects, thus it would behoove *T. gondii* to increase host activity and decrease fear of open spaces. Hutchison et al. performed a series of tests to investigate this hypothesis. The authors looked at three groups of mice infected with *Toxoplasma*: one group was infected and the other two groups were infected congenitally. In the two congenitally infected groups, one was infected before mating and the other was infected during gestation. These mice were then compared with uninfected mice. Each mouse was tested in a box, the floor of which was marked off into 16 equal squares, and its activity was measured over 10 minutes by counting the number of times the mouse entered each square. Behavior was categorized as moving, rearing, digging, grooming and immobility. The results demonstrated that infection with *Toxoplasma* was associated with an increase in the amount of general movement but decreased rearing and digging. This demonstrated that the effect *T. gondii* has on behavior is selective. In addition to increased activity, specifically an increase in short bouts of behavior type, infected mice showed a relative preference for being in the more exposed or new areas of the apparatus boxes [4–6]. These behaviors were not felt to be fully explained by behavioral abnormalities such as lowered motivation or general debility as it would be unlikely for these traits to consistently produce increased levels of activity. It is theorized that *Toxoplasma*infected mice interact with their environment and the stimulation arising from it in a different way than uninfected mice. Furthermore, this study highlighted that the mode of infection, whether congenital or latent did not differ from the behavioral changes noted in infected mice as all infected mice, irrespective of the mode of infection, showed increased activity compared to uninfected controls [5].

*Understanding the Effects of Toxoplasmosis on Host Behavior, Personality, and Cognition DOI: http://dx.doi.org/10.5772/intechopen.108009*

Webster et al. then performed a series of experiments assessing the effects of *Toxoplasma* on rats. Rats are unlike mice in that they exhibit neophobic behavior or the avoidance of new stimuli. Webster et al. used four groups of rats: two groups were placed in cages where the rat's reaction to three food-related novel stimuli (odor, food container, and food) was performed. The other two groups underwent a trappability study to evaluate whether *Toxoplasma* affected the probability of capture. The authors noted that the mice demonstrated low neophobia and that low neophobia was significantly associated with positive *Toxoplasma* titer in three out of four groups of rates. Additionally, *Toxoplasma*-infected rats were more susceptible to trapping and poisoning during post-control programs [7].

Webster et al. then went on to test the correlation and relationship between parasite transmission and load with rat behavioral changes. He sought to understand two things: (1) whether parasites with indirect life cycles, will influence the activity of the intermediate host, increasing the likelihood of transmission and (2) whether the change in observed activity would be an increase in activity rather than a decrease. The authors used four groups of mice: one group were wild brown rats infected with naturally occurring parasites, another was a hybrid of wild and laboratory rats that were experimentally infected with *T. gondii* as adults, another was wild and laboratory rats that were experimentally infected with *T. gondii* congenitally, the last group were rats where were infected with *Syphacia muris*. The difference between *T. gondii* and *Syphacia muris* is that *T. gondii* has an indirect life cycle and *Syphacia muris* has a direct life-cycle parasite. The rats were also matched with uninfected hybrid rats. In the wild occurring rats, out of the six-parasite species detected, *T. gondii* was the only parasite to be associated with higher activity levels when comparing infected rats to uninfected rats. The hybrid rats also experienced increased activity levels compared with uninfected rats. Lastly, there were no differences in activity levels noted between the rats infected with *Syphacia muris* compared with uninfected mice. This study provided evidence that the indirect life-cycle of *T. gondii* can influence the activity of an intermediate host, such as the rat [8].

One of the most profound effects of *T. gondii* infection is the ability to minimize and or eliminate the natural aversion to the odor of predators. In the wild, rodents are at risk of being attacked and eaten by many species, including cats, foxes, and mink. Because of this, rodents have developed an evolutionally innate aversion to the odor of these predators, decreasing their risk of predation [9]. Even laboratory rodents maintain this aversion. Though this aversion to host, particularly cat urine, presents itself as an obstacle to parasites with indirect life cycles such as *T. gondii*. Experiments performed by Berdoy et al. were some of the first to demonstrate *T. gondii*'s ability to alter this aversion to cat odor and decrease the predatory risk of cats, now coined "fatal feline attraction." To test this theory, the authors performed a nocturnal exploratory test on the behavior of rats in outdoor pens. All outdoor pens were covered in a neutral homogeneous and neutral surface. In each corner of the outdoor pen, drops of four distinct types of smells were placed: the rat's urine, cat urine, rabbit urine (served as a control for a mammalian non-predator), and water (neutral smell). The authors noted a significant difference in the behavior of *Toxoplasma*-infected and *Toxoplasma*uninfected rats where uninfected rats maintained an aversion to predatory urine, while infected rats showed a preference for areas containing cat urine. Both groups of rats behaved similarly to the smell of their urine, water, and rabbit odor. The authors concluded that this potentially fatal attraction was not a gross impairment of olfactory senses, but rather a subtle change in the cognitive perception of the host in the face of predatory risk [10]. The findings of Berdoy et al. have been replicated in other

studies [11–13]. Kaushik et al. further demonstrated that this "fatal feline attraction" is not specific to just one feline species, but is exhibited by both domestic cats and wild cats. The authors also reported the interesting finding that not all feline odors were equal but *Toxoplasm*a-infected rats had a stronger preference for wild cat odor over that of domestic cats. This effect did not differ significantly according to the type of wild cat odor used (cheetah or puma) [9].

#### **2.3 Large animals**

*T. gondii*'s effect on behavior expands across a broad range of warm-blooded species. In a study performed by Gering et al., they showed that *T. gondii* can affect the behavior of hyenas (*Crocuta crocuta*) and their naturally occurring interactions with lions (a feline species). Out of the 166 surveyed hyenas, 108 had IgG antibodies to T*. gondii*. The other hyenas were determined to either be uninfected or doubtful to be infected with *Toxoplasma*. From a demographic standpoint, the only differences noted between infected and uninfected hyenas were that infection rates were lowest in cubs (35%), followed by subadults (71%) and adults had the highest rate of infection (80%). They then investigated the association of *T. gondii* infection with boldness toward lions which was determined by their minimum approach distance to the lion(s). Cubs and adult hyenas were analyzed separately because older hyenas consistently approach lions more closely than cubs. Infected cubs had a shorter minimum approach distance from lions (−3.19, 95% CI: −5.57 − 0.81]) than their uninfected counterparts, though for subadults and adults, infection was not related to minimum approach distance. Lastly, the authors assess the association *between T. gondii* infection with lion-related mortality. Among 33 mixed-age hyenas with known mortality causes, infected hyenas were nearly twice as likely to die by lions than by other known causes (52% vs. 25%). When translated into odds, infected hyenas were 3.91 times more likely to die by lions compared with uninfected hyenas, though this funding was not statistically significant (95% CI: 0.70–32.78; *P* = 0.15). In a sub-analysis performed on the 11 cubs infected with *T. gondii*, 100% of the deaths were caused by lions, while only 17% of the uninfected cub deaths were caused by lions. The authors concluded that *T. gondii* infection was associated with behavioral boldness that brought infected hyena cubs into closer proximity to lions, increasing the likelihood of being killed by lions [14].

Recently, mild red foxes have been demonstrated to show uncharacteristic behavior which has been classified as Dopey Fox Syndrome (DFS). These behaviors include an apparent lack of fear, increased affection, constant pacing, facial muscle twitching, and anorexia. Conditions such as encephalitis as well as visual abnormalities and/or blindness which are consistent with *Toxoplasma*, raise the possibility of *T. gondii* being a causative agent. Milne et al. investigated the association between *T. gondii* and/or other neurotropic agents, with DFS. Serology and PCR targeting *T. gondii* were used to determine Toxoplasma infection and a multiplex PCR was developed to test for other neutropenic agents. Some examples of the other neurotropic agents used include canine-specific circovirus, a fox-specific circovirus, canine herpes virus, canine distemper virus, and canine adenovirus type 1 and 2. Results were compared between foxes with DFS maintained in welfare facilities to foxes provided by local pest-control agencies, which the authors referred to as "pseudo-control" foxes. The authors noted that the prevalence of *T. gondii* infection was higher in captive foxes (33%) compared with pseudo-control foxes (6.6%). In the behavioral analysis, the results indicated that *Toxoplasma*-infected foxes preferred cat odor zones compared to dog odor zones.

#### *Understanding the Effects of Toxoplasmosis on Host Behavior, Personality, and Cognition DOI: http://dx.doi.org/10.5772/intechopen.108009*

Additionally, noted was a lack of fear of humans and increased inquisitiveness among *Toxoplasma*-infected captive foxes. The authors though did also find evidence of possible co-infection with other agents playing a role in DFS. In a small sample of captive and pseudo-control foxes that were euthanized (occurred outside of the study setting), there was a higher prevalence of *Toxoplasma* and fox-specific circovirus co-infection in captive foxes (33%) compared with pseudo-control foxes (11%). Co-infection was also associated with aberrant fox behavior, suggesting possible synergy between these two agents that contribute to the presence of DFS [15].

There is a suggestion that the effects of *T. gondii* on human dates back to when our ancestors were still under significant feline predation. Poirotte et al. evaluated whether or not chimpanzees, the human's closest relative, experienced any attraction to feline urine. They found that *Toxoplasma*-infected chimpanzees have lost their innate aversion toward the urine of leopards, who are their only natural predator. This finding seemed to be selective for *T. gondii* as there were no significant differences in the response of *Toxoplasma*-infected and *Toxoplasma*-uninfected chimpanzees toward urine collected from other definitive feline hosts that chimpanzees do not encounter in nature [16]. It is plausible these behavioral modifications could increase the probability of chimpanzee mortality by leopards for the parasite's benefit.

## **3. Toxoplasmosis effect on human personality and behavior**

#### **3.1 Role of toxoplasma on human behavior and personality**

Toxoplasmosis is known to affect the activity of rodents, though there are also well-established studies implicating an association between Toxoplasmosis and human behavioral changes. Toxoplasmosis in humans can be in three forms: congenital, acute, or chronic. Several studies outline the devasting effects Toxoplasmosis can have on a fetus, ranging from hydrocephalus, chorioretinitis, and intracranial calcifications to fetal demise. Reduced intellection function has been reported in approximately 6–9% of children with congenital toxoplasmosis [6, 17–19]. Acute infection has been associated with psychosis confusion, aphasia, and other space-occupying neurologic symptoms [20, 21]. There has been increasing interest in the role that chronic or latent infection has on human personality and behavior.

Flegr et al. performed some of the early studies looking at the role latent toxoplasmosis plays in personality changes. One of his first studies looked at the correlation between serologic evidence of *T. gondii* and personality using the Cattell's personality test among 338 individuals. The authors reported a correlation between *Toxoplasma* and two personalities: lower scores of low superego strength (disregards rules, expedient) and higher scores of Protension (suspecting, jealous, dogmatic). This finding was particularly seen in males [22]. The authors further expanded their study by looking at 224 men and 170 women. In men, they noted similar personality shifts as the prior study, though in addition guilt proneness (apprehensive, self-reproaching, insecure) and group dependency (sociably group dependent, "joiner") were also positively influenced in *Toxoplasma*-infected men. In women, shifts in personality traits include an increase in affectothymia (warm-hearted, outgoing, easygoing), alaxia (trusting, accepting conditions, tolerant), untroubled adequacy (self-assured, placid, secure, complacent), and self-sufficiency (self-sufficient, resourceful, prefers own decisions). The authors wanted to tease out if the association between *Toxoplasma* infection and personality traits were a result of toxoplasmosis inducing the personality shift

or if certain personality factors increased the likelihood of becoming infected with *T. gondii*. To understand this better, the authors examined the personality profiles of 164 male patients who were diagnosed with acute toxoplasmosis within the past 13 years. They were able to conclude that the positive correlation between the duration of latent toxoplasmosis and the intensity of superego strength decrease (*P* < 0.020) suggested that the decrease of superego strength (the willingness to accept group moral standards) was induced by *T. gondii* infection [23]. While the results of these studies are interesting and intriguing, others have criticized the selection methods of the population, the interpretation of the data, and the fact that the results have not been duplicated to date [6]. In later studies, using Cloninger's TCI personality tests, *Toxoplasma*-infected individuals demonstrated decreased scores on factor NS (novelty seeking). This means that individuals had a lower tendency to search for new stimuli, which was seen in both men and women [24–26]. Decreased novelty-seeking scores have been associated with increased concentration of dopamine in the brain tissue, which is consistent with the increased levels of dopamine since in the brain tissue of infected mice [25, 27].

Prolonged reaction time secondary to latent toxoplasmosis has been well established in rodents, though there is increasing data highlighting this same phenomenon of impaired psychomotor performance in humans. One such study was performed by Flagr et al. where increased human activity was associated with increased traffic accidents. The authors conducted a retrospective study assessing the association between toxoplasmosis infection and traffic accidents. The participants included 146 who experienced a traffic accident to 446 persons in the general population. While the seroprevalence of toxoplasmosis varied by age, latent toxoplasmosis was significantly higher in the traffic accident set (*P* < 0.0001). The authors discovered that subjects with latent toxoplasmosis had 2.65 times higher risk of a traffic accident than the toxoplasmosis-negative subjects (95% CI: 1.76–4.01). It is proposed that the prolongation of reaction times caused by toxoplasmosis increases the risk of incidents such as traffic accidents [28]. Additional behavioral adaptations seen in patients with Toxoplasmosis include impaired long-term concentration, lower tidiness in *Toxoplasma*-infected males, lower sociability scores in *Toxoplasma*-infected males, and decreased altruism [29, 30].

#### **3.2 The role of toxoplasma on neuropsychiatric conditions**

Since the 1950s, it was noted that the prevalence of toxoplasmosis among psychiatric patients, especially patients with schizophrenia, was unusually high, implicating that *Toxoplasma gondii* may play a role in the origin and progress of psychiatric diseases [31, 32]. Furthermore, it has been suggested that the effect of latent toxoplasmosis on the risk of schizophrenia is stronger than that of any schizophrenia-associated gene variant identified in genome-wide analyses [33]. It has also been shown that *Toxoplasma*-infected patients with schizophrenia have more severe symptoms of hallucinations and delusions than *Toxoplasma*-free schizophrenia patients and there are structural differences in the brain between *Toxoplasma*-infected schizophrenia patients and *Toxoplasma*-free schizophrenia patients [34]. *Toxoplasma*infected patients have a reduction in gray matter volume bilaterally when compared with *Toxoplasma*-free patients [35, 36]. Other mental health conditions that have been associated with Toxoplasmosis include autism attention deficit hyperactivity disorder, obsessive–compulsive disorder, antisocial personality disorder, learning disabilities,

and anxiety disorders. The association between *T. gondii* and neuropsychiatric disorders will be more extensively explored in a later chapter.

#### **3.3 Toxoplasma and neurodegenerative diseases**

*Toxoplasma* can affect not only personality and behavior but can also contribute to neurocognitive dysfunction. Guenter et al. investigated the cognitive performance of infected young adults using a set of neuropsychological tests. The authors observed trends toward reduced cognitive functions but the differences did not amount to statistical significance [37]. Neurocognitive dysfunction though may be more prominent in older adults. Gajewski et al. conducted a double-blinded neuropsychological study on seniors with asymptomatic latent infection. The authors compared 42 individuals aged greater than 65 with a positive anti-*Toxoplasma* IgG to 42 individuals of the same age range that were negative for toxoplasmosis. Using a computer-based working-memory test (2-back) and several standardized psychometric tests of memory and executive cognitive functions, they determined that *Toxoplasma*-positive seniors showed an impairment of different aspects of memory. In *Toxoplasma*-positive seniors, working memory was decreased by about 35% (*P* = 0.020), they had a lower performance in a verbal memory test, both regarding immediate recall (10% reduction; *P* = 0.022), delayed recognition (6%; *P* = 0.037) and recall from long-term memory assessed by the word fluency tests (12%; *P* = 0.029). Executive functions though were not different among the two groups [38]. Hann et al. confirmed similar findings in their meta-analysis. The meta-analysis included 13 studies, comprising a population of 13,289 healthy participants with a mean age of 47. *Toxoplasma*-negative individuals performed more favorably in four cognitive domains: processing speed (*P* = 0.001), working memory (*P* = 0.002), short-term verbal memory (*P* < 0.001), and executive functioning (*P* = 0.030) [39]. Findings of this study suggest that *Toxoplasma* seropositivity is associated with mild cognitive impairment in several cognitive domains.

These findings led to further investigation into the effect *Toxoplasma* has on neurocognitive disorders, in particular, Alzheimer's disease (AD). AD results from a reduced amount of beta-amyloid plaque deposition and irreversible loss of neurons in the brain. The clinical consequence is gradual loss of memory, increasing impairment of language and other cognitive functions, and later stages with motor dysfunction and inability to perform activities of daily living [40]. Early studies did not demonstrate an association between Toxoplasmosis infection and AD. Mahami-Oskouei et al. performed a case–control study that included 75 patients with AD and 75 negative control patients and they aimed to assess if there was any correlation between toxoplasmosis infection and AD. Toxoplasmosis infection was defined as evidence of a positive anti-*Toxoplasma* IgG. Among the participants, 61.3% of Alzheimer's patients and 62.6% of healthy volunteers were positive for anti-*Toxoplasma* IgG, but all participants were negative for anti-*Toxoplasma* IgM. Their analysis did not demonstrate any significant differences between Alzheimer's patients with their controls in terms of anti-*Toxoplasma* IgG antibody (*P* = 0.5) [41]. In the same year, Perry et al. noted similar findings. Their study included 105 subjects with AD and 114 controls. Anti-*Toxoplasma* IgG antibodies were present in 41% of the AD group and 33% in the control group. They too found no association with either the prevalence of anti-*Toxoplasma* IgG antibodies among the two groups (*P* = 0.25) or the log-transformed antibody concentration (*P* = 0.85) [42].

However, two recent meta-analyses demonstrated an association between *Toxoplasma* and AD. Chegeni et al. meta-analysis investigating the possible association between *T. gondii* and AD included 8 articles. They conducted a random effects model to determine the odds ratio (OR). The results showed a common OR of 1.53 (95% CI: 1.07–2.18). They concluded that *T. gondii* can be considered a risk factor for the development of AD and exacerbation of its symptoms. It was acknowledged that three studies mainly drove the results of the meta-analysis, thus with the small number of published relevant studies being low, the risk of the presence of publication bias is relatively high [43]. Bayani et al. looked at the association between *Toxoplasma*, AD, and Parkinson's Disease. Parkinson's Disease (PD) is a neurologic condition that affects movement, often causing stiffness, tremors, and difficulty with balance and coordination. They included 11 studies (7 for PD and 4 for AD). The meta-analysis showed no statistically significant association between the presence of anti-*Toxoplasma* IgG antibody and increased risk of Parkinson's disease (OR, 1.14; 95% CI: 0.78–1.68), though the OR for the association of the presence of anti-*Toxoplasma* IgG antibody with Alzheimer's patients, compared to control group, was (OR, 1.38; 95% CI: 0.99–1.92). The authors concluded that there was a marginally significant association between *Toxoplasma* infection and Alzheimer's disease [44].

The varying results found in studies could in part be explained by *Toxoplasma* having differential effects on cognition throughout one's lifespan. Given that neurodegeneration is generally seen at an older age, on average elderly seropositive adults have been infected for much longer than younger individuals. This allows for the indirect effects of latent toxoplasmosis to further exacerbate inflammation and neurodegeneration [45]. The mechanisms of direct and indirect effects of *Toxoplasma* will be further examined in the following section.

#### **4. Mechanisms of toxoplasma affect human behavior**

#### **4.1 Mechanism of action for cognitive effects of toxoplasma**

Dopamine is a neurotransmitter that is directly involved in the regulation of cognitive processes. It has been demonstrated that *T. gondii* increases the concentration of dopamine in the brain of infected hosts, including humans, through increasing dopaminergic signaling during both acute and latent infection [24, 45]. For these reasons, it is assumed that dopamine drives many of the associated neurocognitive observations in individuals with toxoplasmosis. Two main mechanisms seem to be at play that affects cognitive function: increased catecholamine synthesis leading to increased dopamine release (these are referred to as direct effects) and chronic inflammation leading to impaired dopaminergic neurotransmission and neurodegeneration (these are referred to as indirect effects).

Dopamine is produced in two steps from its precursor tyrosine. In the first step, tyrosine hydroxylase (TH) converts tyrosine into L-DOPA. In the second step, DOPA decarboxylase converts L-DOPA into dopamine. Any increase in the conversion of tyrosine to L-DOPA will result in increased dopamine synthesis. This is important because Gaskell et al. discovered that the genome of *T. gondii* contains two genes encoding tyrosine hydroxylase and this protozoan enzyme encompasses catalytic properties similar to those of the TH found in mammalian cells (Gaskell et al., 2009) [46]. TH is produced by *T. gondii* during the formation of the bradyzoites of the cyst stages of the life cycle. This increased production of TH is selectively

*Understanding the Effects of Toxoplasmosis on Host Behavior, Personality, and Cognition DOI: http://dx.doi.org/10.5772/intechopen.108009*

specific to transmitters derived from tyrosine/L-DOPA leaving those that are not unaffected [45].

Further evidence that dopaminergic signaling is indeed the most likely cause of *Toxoplasma*-associated alterations of behavior and cognition is that dopaminergic antagonists like haloperidol seem to normalize *Toxoplasma*-induced behavioral changes in infected rodents [11, 47]. Skallova et al. examined if the behavioral response of *Toxoplasma*-infected male and female mice would be attenuated when given a selective dopamine uptake inhibitor, GBR 12909. Both genders of *Toxoplasma*infected mice had decreased locomotor activity and decreased locomotion in the open field. Infected females displayed an increased level of exploration in the hole board test. GBR 12909 induced suppression in hole board-exploration in the infected males mitigating the effects of toxoplasmosis, but had an opposite effect on the controls [47]. Webster et al. performed a similar study, using haloperidol and/or valproic acid (an anti-psychotic and mood stabilizer, respectively. These medications are used in the treatment of mental illnesses, including schizophrenia. The authors discovered that anti-psychotic drugs were as effective as anti-T. gondii drugs in preventing behavioral changes secondary to toxoplasmosis [11].

Indirect mechanisms of action of *T. gondii* involve the use of inflammatory markers that modulate neurotransmission and associated cognitive processes. To keep *T. gondii* in the latent phase of toxoplasmosis, the immune system enhances the production of proinflammatory cytokines. The release of these substances not only prevents the dissemination of toxoplasmosis, but also impacts the levels, turnover, and efficiency of many neurotransmitters including dopamine, glutamate, and serotonin. This chronic overactivation of the immune system in response to latent infection compounded with the general effects of aging likely progresses and accelerates neurodegeneration [45]. A summary of the possible direct and indirect mechanisms and neurophysiological changes induced by chronic *T. gondii* is shown (**Figure 1**—originally published by Tedford et al).

#### **4.2 Role of rhesus blood group**

The effect of toxoplasmosis on personality and performance may also be in part secondary to a specific Rh blood type. Several studies that have been performed on pregnant women and military personnel have shown that RhD blood group positivity, especially in RhD heterozygotes, protects against various effects of latent toxoplasmosis [48–51]. Novotná et al. and Flegr et al. both noted in their respective studies that Rh-positive subjects, and RhD-positive heterozygotes, in particular, were protected against latent toxoplasmosis-induced impairment of reaction times [48, 50]. Flegr et al. also noted in a prospective study that included nearly 4000 military drivers, that Rh-negative *Toxoplasma*-infected subjects had about three times higher probability of a traffic accident than Rh-negative *Toxoplasma*-free individuals or Rh-positive individuals [49]. This finding was noted regardless of whether the Rh-positive subjects were *Toxoplasma*-free or *Toxoplasma*-infected. Lastly, Kankova et al. detected that RhD-positivity might protect infected pregnant women from excessive gestational weight gain [51].

Flegr et al. further assess the association between toxoplasmosis and the personality of RhD-negative and RhD-positive subjects. The study included 502 male soldiers of Czech nationality who underwent several tests including the N-70 questionnaire, the NEO-PI-R questionnaire, the Wiener Matrizen-Test (WMT) test of intelligence, and the OTIS test intelligence. The authors noted that *Toxoplasma*-infected subjects

#### **Figure 1.**

*Directly and indirectly mediated effects of chronic T. gondii infection on host neurophysiology. Model of mechanisms involved with host responses to infection (i.e., neuroimmune and hormonal changes) indirect and more likely confounding factors, augmenting neurophysiological changes rather than inducing them. Indeed, the specificity of behavioral changes associated with infection suggest that direct mechanisms of the parasite–host interaction play a significant role in the neurophysiological changes associated with chronic T. gondii infection.*

scored lower in the total N-70 score and also in anxiety, depression, phobia, hysteria, and vegetative lability, and in the NEO-PI-R (Big Five) trait neuroticism. The differences were much stronger in RhD-negative than RhD-positive subjects. Additionally, the RhD-positive, *Toxoplasma*-infected subjects express lower verbal and nonverbal intelligence than their *Toxoplasma-*free peers. Though RhD-negative, *Toxoplasma*infected persons expressed higher verbal and nonverbal intelligence compared with *Toxoplasma-*free peers [52].

In contrast to the findings in this study, an earlier study performed on University students noted differing results. In that study, there was no difference in expression of neuroticism between *Toxoplasma*-infected and *Toxoplasma-*free students [53]. The fact that *Toxoplasma*-infected soldiers in the Flegr et al. study expressed lower and not higher levels of psychopathognomic traits as measured by the N-70 questionnaire, was also different than in the prior study [53]. Flegr et al. went on further to determine whether the effects of RhD phenotype were exclusive to *Toxoplasma*-infected individuals or whether it influences the effects of other factors. The authors determined that the RhD phenotype modulates the influence not only of latent toxoplasmosis but also factors such as age and smoking, on human behavior and physiology. This suggests that the different human behaviors and physiology seen between RhDpositive *Toxoplasma*-infected persons and RhD-negative *Toxoplasma*-infected persons may be more related to the RhD status than the presence of *Toxoplasma* itself [54].
