**3. The role of** *T. gondii* **in the etiopathogenetic of psychiatric diseases**

Any infectious agent can affect neurons and brain structures after activation of the proinflammatory immune response and neurotransmitters, thus causing psychosis. Among the different infectious agents, *T. gondii* has received more attention for its location in the CNS. Many studies have suggested that toxoplasmosis is a risk factor for the development of behavioral changes and neuropsychiatric disorders such as depression, Schizophrenia, Alzheimer and Parkinson diseases. During an acute infection, the parasite is mainly present in peripheral tissues and blood, but also has access to the brain via immune circulating cells, as is explained in the part of *Regulation of the cerebral immune mechanism during T. gondii infection*. An early feature of *T. gondii* brain infection is the activation of glial cells, particularly astrocytes and microglia [24, 25, 46]. *Toxoplasma* cysts reside in the brain during latent infection. In individuals with acquired immune deficiencies, e.g., AIDS, or undergoing prolonged immunity, suppressive treatments, reactivation of the infection can lead to toxoplasmic encephalitis, also calling for cerebral toxoplasmosis. In recent years it has been shown that the latent toxoplasmosis, although often rejected as asymptomatic and clinically unimportant, can modify host behavior in human and rodents. This parasite has the capacity to be an etiological factor for some neuropsychiatric diseases [47].

A bunch of data hypothesizes that latent toxoplasmosis may be a risk factor for the depression. The low-grade inflammation caused by the chronic *Toxoplasma* infection it could be related to the development of behavioral symptoms, but the results have been varied multifactorial [48]. Regarding, the possible relationship between *Toxoplasma* infection and depression, study shows that specific *Toxoplasma* IgG titer levels correlated positively with depression [49]. One study found that this infection affected susceptibility to depression and severity of depressive symptoms in pregnant women [50]. Another study showed that male subjects infected with *Bartonella henselae* displayed more severe depressive symptoms when co-infected with *T. gondii* [51] but Pearce and collaborators, Sutterland and collaborators concluded that there is not any relationship between *T. gondii* infection and depression [52, 53]. Psychiatric patients with primarily severe or very severe depression are displaying more severe symptoms when are infected with *T. gondii*. In this recent study, results suggest that *Toxoplasma* infection can be related to anxiety, burnout and potentially to the severity of depression [48]. The possible link between *T. gondii* infection and Parkinson diseases is controversial. Tissue cysts of *T. gondii* reside especially in the amygdala, olfactory bulbs, hippocampus, cortical regions, and hypothalamus and could actively inhibit neuronal function in chronically infected mice [54]. Tachyzoite infection of neurons resulted in a dysregulated Ca2+ influx upon stimulation with glutamate, the major excitatory amino acid in the CNS leading either too hyper- or hypo-responsive neurons. Other experiments indicate that tachyzoites deplete Ca2+ stores in the endoplasmic reticulum that may contribute to the altered behavior of the host [54]. In addition, alteration of neurotransmitter pathways, degradation of dopamine-producing nerve cells and neurogenic inflammation induced by *T. gondii* infection are mentioned as etiology that could eventually lead to Parkinson disease [55]. Regarding the effect of *Toxoplasma* on the production of dopamine (DOPA) in the brain, studies have shown that this parasite-induced high concentrations of DOPA and tyrosine hydroxylase (TH)

**123**

Toxoplasma *Immunomodulation Related to Neuropsychiatric Diseases*

section presents an overview of the explanations published.

**3.1 The cerebral immune response activated during schizophrenia** 

In cerebral toxoplasmosis, the balance between host immunity and defense mechanisms in the event of parasite escape is the basis of asymptomatic infection. Inflammation and immune deregulation have consistently been observed in both *Toxoplasma* infection and Schizophrenia. In the acute phase of infection, Th1 proinflammatory reaction is promoted by cytokines released in CNS to control parasite multiplication, this reaction was controlled by activation of Th2 immune reaction to minimize local cerebral inflammation. This immune response enhances the multiplication of parasite and promotes persistence of *Toxoplasma* tissue cysts in neuronal and glial cells. In Schizophrenia, an imbalance Th1 and Th2 reaction have shown with major activation of Th2 immune response and production of IL-6 and IL-10 [60]. IFN-γ, IL-12, TNF-α, IL-4 and IL-10, together with IL-1 and IL-1β, IL-2, IL-6, granulocytes (GM-CSF and GSF), IL-17 and IL-23 are variably expressed by astrocytes, microglial cells, neuron, TCD4+ and TCD8+ cells [9, 13, 31, 41–43] (**Figure 1**). All these immune mediators have shown to be markers for acute exacerbations of Schizophrenia [60]. This immune system can influence mood and behavior through their ability to modulate neurotransmission; therefore, the idea that latent infection is clinically asymptomatic may be associated with neuropsychiatric disorders. Since tachyzoites induce inflammatory tropism in host cells more than bradyzoites, the proliferation of tachyzoites in the brain after cyst rupture may be related to the onset of Schizophrenia and other mental illnesses [61]. In people with acute Schizophrenia, the display of symptoms has increased responses to cytokines. With regard to cytokine-induced effects, the role of IL-1β and IFN-γ in the activation of astrocytes have a major role. These immune proteins induce activation of astrocytes and microglia cells to inhibit tachyzoite replication by producing high levels of NO. In addition, experimental studies in rodents have shown that TCD8+ cells play a central role in longterm immunity to *Toxoplasma*. Depletion of CD8+ T cells may cause reactivation of latent disease in later phases of chronic toxoplasmosis. Interest in the potential correlation to this observation is the regulation of TCD8+ lymphocytes typically observed in schizophrenic patients [62]. After a short acute toxoplasmosis phase, the infection becomes latent and becomes encysted in the central nervous system and muscle tissue, probably throughout the life of the infected host. Evidence suggests that the parasite affects the synthesis of neurotransmitters, particularly DOPA, in infected individuals, which could lead to neurological and psychiatric disorders [63]. In addition to the studies that directly indicated the association between *Toxoplasma* infection and the increased incidence of Schizophrenia,

in CNS [56]. Parkinson disease is associated with lower levels of DOPA. So, the association between *Toxoplasma* infection and neuropsychiatric disorders could be strongly related to Schizophrenia but not Parkinson's disease [57]. Evidence suggests that *T. gondii* could be an etiological factor for Schizophrenia. Clinically, latent toxoplasmosis and Schizophrenia both induce similar alteration in brain morphology: gray matter atrophy, loss of brain parenchyma, ventricle system enlargement, CD4+ and CD8+ T cell influx, pro-inflammatory immune system infiltration, dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion, which may deal with *T. gondii*-induced behavioral change [47, 58, 59]. Indeed, the relationship between chronic or acute *Toxoplasma* infection and Schizophrenia seems to exist. Researches in this field are increasing to determine the existence of this association by epidemiological, medical and biological studies. The following

*DOI: http://dx.doi.org/10.5772/intechopen.86695*

**and** *T. gondii* **infection**

Toxoplasma *Immunomodulation Related to Neuropsychiatric Diseases DOI: http://dx.doi.org/10.5772/intechopen.86695*

*Parasitology and Microbiology Research*

neuropsychiatric diseases [47].

(E/SA) [45].

of infection. This is confirmed by the neutralization of this cytokine in *T. gondii*infected mice [44] and following vaccination of the mice with *T. gondii* antigens

**3. The role of** *T. gondii* **in the etiopathogenetic of psychiatric diseases**

Any infectious agent can affect neurons and brain structures after activation of the proinflammatory immune response and neurotransmitters, thus causing psychosis. Among the different infectious agents, *T. gondii* has received more attention for its location in the CNS. Many studies have suggested that toxoplasmosis is a risk factor for the development of behavioral changes and neuropsychiatric disorders such as depression, Schizophrenia, Alzheimer and Parkinson diseases. During an acute infection, the parasite is mainly present in peripheral tissues and blood, but also has access to the brain via immune circulating cells, as is explained in the part of *Regulation of the cerebral immune mechanism during T. gondii infection*. An early feature of *T. gondii* brain infection is the activation of glial cells, particularly astrocytes and microglia [24, 25, 46]. *Toxoplasma* cysts reside in the brain during latent infection. In individuals with acquired immune deficiencies, e.g., AIDS, or undergoing prolonged immunity, suppressive treatments, reactivation of the infection can lead to toxoplasmic encephalitis, also calling for cerebral toxoplasmosis. In recent years it has been shown that the latent toxoplasmosis, although often rejected as asymptomatic and clinically unimportant, can modify host behavior in human and rodents. This parasite has the capacity to be an etiological factor for some

A bunch of data hypothesizes that latent toxoplasmosis may be a risk factor for the depression. The low-grade inflammation caused by the chronic *Toxoplasma* infection it could be related to the development of behavioral symptoms, but the results have been varied multifactorial [48]. Regarding, the possible relationship between *Toxoplasma* infection and depression, study shows that specific *Toxoplasma* IgG titer levels correlated positively with depression [49]. One study found that this infection affected susceptibility to depression and severity of depressive symptoms in pregnant women [50]. Another study showed that male subjects infected with *Bartonella henselae* displayed more severe depressive symptoms when co-infected with *T. gondii* [51] but Pearce and collaborators, Sutterland and collaborators concluded that there is not any relationship between *T. gondii* infection and depression [52, 53]. Psychiatric patients with primarily severe or very severe depression are displaying more severe symptoms when are infected with *T. gondii*. In this recent study, results suggest that *Toxoplasma* infection can be related to anxiety, burnout and potentially to the severity of depression [48]. The possible link between *T. gondii* infection and Parkinson diseases is controversial. Tissue cysts of *T. gondii* reside especially in the amygdala, olfactory bulbs, hippocampus, cortical regions, and hypothalamus and could actively inhibit neuronal function in chronically infected mice [54]. Tachyzoite infection of neurons resulted in a dysregulated Ca2+ influx upon stimulation with glutamate, the major excitatory amino acid in the CNS leading either too hyper- or hypo-responsive neurons. Other experiments indicate that tachyzoites deplete Ca2+ stores in the endoplasmic reticulum that may contribute to the altered behavior of the host [54]. In addition, alteration of neurotransmitter pathways, degradation of dopamine-producing nerve cells and neurogenic inflammation induced by *T. gondii* infection are mentioned as etiology that could eventually lead to Parkinson disease [55]. Regarding the effect of *Toxoplasma* on the production of dopamine (DOPA) in the brain, studies have shown that this parasite-induced high concentrations of DOPA and tyrosine hydroxylase (TH)

**122**

in CNS [56]. Parkinson disease is associated with lower levels of DOPA. So, the association between *Toxoplasma* infection and neuropsychiatric disorders could be strongly related to Schizophrenia but not Parkinson's disease [57]. Evidence suggests that *T. gondii* could be an etiological factor for Schizophrenia. Clinically, latent toxoplasmosis and Schizophrenia both induce similar alteration in brain morphology: gray matter atrophy, loss of brain parenchyma, ventricle system enlargement, CD4+ and CD8+ T cell influx, pro-inflammatory immune system infiltration, dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion, which may deal with *T. gondii*-induced behavioral change [47, 58, 59]. Indeed, the relationship between chronic or acute *Toxoplasma* infection and Schizophrenia seems to exist. Researches in this field are increasing to determine the existence of this association by epidemiological, medical and biological studies. The following section presents an overview of the explanations published.

#### **3.1 The cerebral immune response activated during schizophrenia and** *T. gondii* **infection**

In cerebral toxoplasmosis, the balance between host immunity and defense mechanisms in the event of parasite escape is the basis of asymptomatic infection. Inflammation and immune deregulation have consistently been observed in both *Toxoplasma* infection and Schizophrenia. In the acute phase of infection, Th1 proinflammatory reaction is promoted by cytokines released in CNS to control parasite multiplication, this reaction was controlled by activation of Th2 immune reaction to minimize local cerebral inflammation. This immune response enhances the multiplication of parasite and promotes persistence of *Toxoplasma* tissue cysts in neuronal and glial cells. In Schizophrenia, an imbalance Th1 and Th2 reaction have shown with major activation of Th2 immune response and production of IL-6 and IL-10 [60]. IFN-γ, IL-12, TNF-α, IL-4 and IL-10, together with IL-1 and IL-1β, IL-2, IL-6, granulocytes (GM-CSF and GSF), IL-17 and IL-23 are variably expressed by astrocytes, microglial cells, neuron, TCD4+ and TCD8+ cells [9, 13, 31, 41–43] (**Figure 1**). All these immune mediators have shown to be markers for acute exacerbations of Schizophrenia [60]. This immune system can influence mood and behavior through their ability to modulate neurotransmission; therefore, the idea that latent infection is clinically asymptomatic may be associated with neuropsychiatric disorders. Since tachyzoites induce inflammatory tropism in host cells more than bradyzoites, the proliferation of tachyzoites in the brain after cyst rupture may be related to the onset of Schizophrenia and other mental illnesses [61]. In people with acute Schizophrenia, the display of symptoms has increased responses to cytokines. With regard to cytokine-induced effects, the role of IL-1β and IFN-γ in the activation of astrocytes have a major role. These immune proteins induce activation of astrocytes and microglia cells to inhibit tachyzoite replication by producing high levels of NO. In addition, experimental studies in rodents have shown that TCD8+ cells play a central role in longterm immunity to *Toxoplasma*. Depletion of CD8+ T cells may cause reactivation of latent disease in later phases of chronic toxoplasmosis. Interest in the potential correlation to this observation is the regulation of TCD8+ lymphocytes typically observed in schizophrenic patients [62]. After a short acute toxoplasmosis phase, the infection becomes latent and becomes encysted in the central nervous system and muscle tissue, probably throughout the life of the infected host. Evidence suggests that the parasite affects the synthesis of neurotransmitters, particularly DOPA, in infected individuals, which could lead to neurological and psychiatric disorders [63]. In addition to the studies that directly indicated the association between *Toxoplasma* infection and the increased incidence of Schizophrenia,

some indirect evidence also highlighted the role of *T. gondii* in the etiology of Schizophrenia. More knowledge about the pathogenesis of the disorder would lead to more effective prevention and treatment strategies.

## **3.2 The neurobiological studies related to** *T. gondii* **infection to schizophrenia disease**

There are differences in *T. gondii* infection; the acute phase and the chronic and phase. Cerebral cysts are formed in the cerebral hemispheres, hippocampus, amygdala, basal ganglia, cerebellum, cerebral cortex, brainstem, and olfactory bulb, and a variety of brain cells that may be infected, including neurons, microglia and mainly astrocytes [46] (**Figure 1**). Encysted *T. gondii* bradyzoites are capable of inhibiting apoptosis and modulates some signaling pathways such as nuclear factor (NF-B), mitogen-activated protein kinase (MAPKinase), phosphoinositide 3 kinase (PI3K)/ PKB/Akt and c-Jun N-terminal kinases (JNK); so that they can persist in host cells for long periods of time [64]. As cysts develop, the host cell degenerates and can break, releasing bradyzoites that can differentiate into tachyzoites, invade and kill surrounding cells, if uncontrolled by the immune system. Especially in immunocompromised patients, the infection is severe, sometimes with hydrocephalus, acute necrotizing encephalitis, and glial nodules formation. Lesions in the brain can manifest as behavioral symptoms by interfering with brain function in the area surrounding the lesion via mass effects or paracrine secretions. This explains the observation of high-concentration tissue cysts in the amygdala and nucleus accumbens, containing dopamine in limbic regions of the brain known to be an important control of motivation, pleasure, dependence, reward, and fear [47]. Other effects are more intriguing; Alteration of the neurotransmitter involves the production of homologous proteins to aromatic amino acid TH and dopamine (DOPA) 2 receptor (D2R) compounds with an increase in DOPA synthesis, tryptophan (TRP) degradation and the decrease in serotonin synthesis [56, 65].

The most likely mechanism of action in Schizophrenia affects neurotransmission in specific brain areas such as the thalamic-cortical limbic circuit of DOPA, 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and glutamate. As a result, schizophrenic patients show abnormal levels of these neurotransmitters. Studies show an increase in DOPA release in the limbic system [47, 66]. In addition, *T. gondii* involves in the etiopathogenesis of Schizophrenia affecting neurotransmitters, especially DOPA [67]. The production *T. gondii* bradyzoites leads to induce liberation of TH, the enzyme that catalyzes the conversion of L-tyrosine (L-Tyr) to L-dihydroxyphenylalanine (L-DOPA) [68] and then L-DOPA is converted to DOPA by the enzyme DOPA decarboxylase. Dopamine is shown to be an essential product that stimulates proliferation and enhance infection and conversion of *T. gondii* in the brain [68]. After the synthesis of DOPA, it is transformed into phenylalanine (Phe) and tyrosine (Tyr) via the activity of phenylalanine hydroxylase (PAH). the elevation of the Phe/Tyr ratio and the alteration of PAH activity is related to the activation of the Th1-type immune response, which is activated during *T. gondii* infection. The increase in DOPA production was originally thought to be a product of inflammation of brain tissue (**Figure 2**). Blood levels of Phe and Tyr were increased in *T. gondii*positive individuals with aggressive personality traits, and in particular those with overt history of aggression and suicidal behavior, so this mechanism could explain the link between Toxoplasmosis and Schizophrenia [69]. The increased concentration of DOPA in specific parts of the brain of patients is presumed to be responsible for the positive symptoms of this mental disorder. However, studies

**125**

Toxoplasma *Immunomodulation Related to Neuropsychiatric Diseases*

have identified two genes for limiting the TH synthesis in the genome of *T. gondii*; these genes expressed in the brain are responsible for DOPA overproduction in *T. gondii* tissue cysts that is responsible for the positive symptoms of some

*Diagram showing the neurobiological pathway related to* T. gondii *infection to schizophrenia disease.*

In addition to DOPA, studies have also evaluated alterations of the kynurenine pathway (KYN) and involvement of TRP [71, 72]. In immunocompetent hosts, infection with *T. gondii* leads to the production of IFN-γ and production of indoleamine 2,3-dioxygenase (IDO), which converts the TRP to KYN and inhibits *T. gondii* growth. The metabolism of Tryptophan generates kynurenine and 3-hydroxykynurenine. The imbalance of these catabolites plays a role in the pathophysiology of Schizophrenia with positive and negative symptoms, which are reversible in response to antipsychotic treatment impact on such imbalance [71]. Additionally, alterations of the KYN pathway have also been shown with an increased KYN/TRP ratio and elevated kynurenic acid (KYNA) levels [73]. Activation of the KYN pathway following *T. gondii* infection may be part of a biological defense strategy against *T. gondii* infections. In the brain, this metabolism pathway takes place mainly in astrocytes that release newly produced KYNA into the extracellular environment, where it can influence surrounding neurons. KYNA synthesis is initiated also by tryptophan dioxygenase (TDO), this enzyme has shown that is elevated in the brains of Schizophrenia patients particularly in astrocytes and glial cells [74]. *T. gondii* infection in the CNS is accompanied, in response to parasite invasion or an inflammatory reaction, by strong activation of astrocytes and glial cells, resulting from high KYNA synthesis in these stimulated cells [75]. This reaction promotes high production of TDO or IDO in the brain and enhances proinflammatory cytokine expression in the site of *T. gondii* infection. These neuro-

biological data relating *Toxoplasma* infection to neuropsychiatric diseases.

*DOI: http://dx.doi.org/10.5772/intechopen.86695*

Schizophrenia patients [70].

**Figure 2.**

Toxoplasma *Immunomodulation Related to Neuropsychiatric Diseases DOI: http://dx.doi.org/10.5772/intechopen.86695*

**Figure 2.**

*Parasitology and Microbiology Research*

in serotonin synthesis [56, 65].

**disease**

some indirect evidence also highlighted the role of *T. gondii* in the etiology of Schizophrenia. More knowledge about the pathogenesis of the disorder would

**3.2 The neurobiological studies related to** *T. gondii* **infection to schizophrenia** 

There are differences in *T. gondii* infection; the acute phase and the chronic and phase. Cerebral cysts are formed in the cerebral hemispheres, hippocampus, amygdala, basal ganglia, cerebellum, cerebral cortex, brainstem, and olfactory bulb, and a variety of brain cells that may be infected, including neurons, microglia and mainly astrocytes [46] (**Figure 1**). Encysted *T. gondii* bradyzoites are capable of inhibiting apoptosis and modulates some signaling pathways such as nuclear factor (NF-B), mitogen-activated protein kinase (MAPKinase), phosphoinositide 3 kinase (PI3K)/ PKB/Akt and c-Jun N-terminal kinases (JNK); so that they can persist in host cells for long periods of time [64]. As cysts develop, the host cell degenerates and can break, releasing bradyzoites that can differentiate into tachyzoites, invade and kill surrounding cells, if uncontrolled by the immune system. Especially in immunocompromised patients, the infection is severe, sometimes with hydrocephalus, acute necrotizing encephalitis, and glial nodules formation. Lesions in the brain can manifest as behavioral symptoms by interfering with brain function in the area surrounding the lesion via mass effects or paracrine secretions. This explains the observation of high-concentration tissue cysts in the amygdala and nucleus accumbens, containing dopamine in limbic regions of the brain known to be an important control of motivation, pleasure, dependence, reward, and fear [47]. Other effects are more intriguing; Alteration of the neurotransmitter involves the production of homologous proteins to aromatic amino acid TH and dopamine (DOPA) 2 receptor (D2R) compounds with an increase in DOPA synthesis, tryptophan (TRP) degradation and the decrease

The most likely mechanism of action in Schizophrenia affects neurotransmission in specific brain areas such as the thalamic-cortical limbic circuit of DOPA, 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and glutamate. As a result, schizophrenic patients show abnormal levels of these neurotransmitters. Studies show an increase in DOPA release in the limbic system [47, 66]. In addition, *T. gondii* involves in the etiopathogenesis of Schizophrenia affecting neurotransmitters, especially DOPA [67]. The production *T. gondii* bradyzoites leads to induce liberation of TH, the enzyme that catalyzes the conversion of L-tyrosine (L-Tyr) to L-dihydroxyphenylalanine (L-DOPA) [68] and then L-DOPA is converted to DOPA by the enzyme DOPA decarboxylase. Dopamine is shown to be an essential product that stimulates proliferation and enhance infection and conversion of *T. gondii* in the brain [68]. After the synthesis of DOPA, it is transformed into phenylalanine (Phe) and tyrosine (Tyr) via the activity of phenylalanine hydroxylase (PAH). the elevation of the Phe/Tyr ratio and the alteration of PAH activity is related to the activation of the Th1-type immune response, which is activated during *T. gondii* infection. The increase in DOPA production was originally thought to be a product of inflammation of brain tissue (**Figure 2**). Blood levels of Phe and Tyr were increased in *T. gondii*positive individuals with aggressive personality traits, and in particular those with overt history of aggression and suicidal behavior, so this mechanism could explain the link between Toxoplasmosis and Schizophrenia [69]. The increased concentration of DOPA in specific parts of the brain of patients is presumed to be responsible for the positive symptoms of this mental disorder. However, studies

lead to more effective prevention and treatment strategies.

**124**

*Diagram showing the neurobiological pathway related to* T. gondii *infection to schizophrenia disease.*

have identified two genes for limiting the TH synthesis in the genome of *T. gondii*; these genes expressed in the brain are responsible for DOPA overproduction in *T. gondii* tissue cysts that is responsible for the positive symptoms of some Schizophrenia patients [70].

In addition to DOPA, studies have also evaluated alterations of the kynurenine pathway (KYN) and involvement of TRP [71, 72]. In immunocompetent hosts, infection with *T. gondii* leads to the production of IFN-γ and production of indoleamine 2,3-dioxygenase (IDO), which converts the TRP to KYN and inhibits *T. gondii* growth. The metabolism of Tryptophan generates kynurenine and 3-hydroxykynurenine. The imbalance of these catabolites plays a role in the pathophysiology of Schizophrenia with positive and negative symptoms, which are reversible in response to antipsychotic treatment impact on such imbalance [71]. Additionally, alterations of the KYN pathway have also been shown with an increased KYN/TRP ratio and elevated kynurenic acid (KYNA) levels [73]. Activation of the KYN pathway following *T. gondii* infection may be part of a biological defense strategy against *T. gondii* infections. In the brain, this metabolism pathway takes place mainly in astrocytes that release newly produced KYNA into the extracellular environment, where it can influence surrounding neurons. KYNA synthesis is initiated also by tryptophan dioxygenase (TDO), this enzyme has shown that is elevated in the brains of Schizophrenia patients particularly in astrocytes and glial cells [74]. *T. gondii* infection in the CNS is accompanied, in response to parasite invasion or an inflammatory reaction, by strong activation of astrocytes and glial cells, resulting from high KYNA synthesis in these stimulated cells [75]. This reaction promotes high production of TDO or IDO in the brain and enhances proinflammatory cytokine expression in the site of *T. gondii* infection. These neurobiological data relating *Toxoplasma* infection to neuropsychiatric diseases.
