**Abstract**

*Toxoplasma gondii* (*T. gondii*) causes toxoplasmic encephalitis resulting from reactivation of latent toxoplasmosis. It is the most frequent clinical manifestation, characterized by multiple necrotizing brain lesions. Bradyzoite tissue cysts activate an immune response that has a major impact on controlling parasite persistence in the brain. The immune mechanisms stimulated in the brain cause a local inflammatory mediated by Th1 immune reaction cytokines. Several studies have linked this process to that active during different neuropsychiatric disorders, such as Schizophrenia. In addition to the immune reaction activated in the brain, this latter has the capacity to stimulate neurotransmitter production. *T. gondii* induces high concentrations of dopamine and tyrosine hydroxylase in the central nervous system and has also been shown to increase kynurenine/tryptophan ratio and elevated Kynurenic acid level, mainly in astrocyte cells. This imbalance plays a role in the pathophysiology of Schizophrenia. Results of different studies explain in this chapter support the idea that *Toxoplasma* is an etiological factor in Schizophrenia.

**Keywords:** *Toxoplasma gondii*, neuropsychiatric disorders, schizophrenia, immunity, neurotransmitter

## **1. Introduction**

Toxoplasmosis is one of the most common parasitic zoonosis in the world. Its causative agent, *Toxoplasma gondii*, is an obligate intracellular protozoan, which has developed several potential pathways for the transmission between different host species. *T. gondii* is able to establish a persistent infection within the brain. In this case, the immunocompetent subject will harbor latent *Toxoplasma* cysts in his central nervous system (CNS). Chronic *Toxoplasma* infection is asymptomatic although studies suggest that it may be a factor associated with chronic neurological conditions (Schizophrenia, Parkinson, bipolar diseases, etc.) [1, 2]. When the infection occurs in a pregnant woman, contamination of the fetus is possible with varying consequences depending on the stage of embryogenesis and the degree of maturity of the immune system. The neurological disorders (hydrocephalus, microcephaly, mental retardation, intracranial calcification) or ocular (retinochoroiditis) of congenital toxoplasmosis reflect the neurological tropism of this parasite [3]. Similarly, during a progressive degradation of the immune system functions following infection with the human immunodeficiency virus (HIV) or immunosuppressive treatment, the brain is the preferred target for the reactivation of latent *Toxoplasma* cysts [4, 5]. Parasite multiplication in the CNS induces a local inflammatory reaction resulting in brain damage and a strong synthesis of neurotransmitters which are involved in necrotizing brain lesions and in neurological disorders. The relationship between *T. gondii* infection and the development of the bipolar disorder (BD) has long been investigated, Evidence studies suggest that this infection may be related to neuropsychiatric disorders, especially Schizophrenia. Immune response has a major role in the persistence of *T. gondii* cysts in the brain. The protective immune reaction against *Toxoplasma* is very complex. During primary infection, the components of the nonspecific immune response occur first. *T. gondii* tachyzoites reach the intestinal lumen, enter the intestinal cells, and multiply in the cells of the lamina propria [6]. At this stage, infected enterocytes activate an immune response to limit parasite multiplication [7]. This response mainly involves neutrophils, macrophages, monocytes and dendritic cells via the secretion of different chemoattractant proteins. Secondarily, cellular immune response is specifically activated against the parasite [8]. It is essentially an immune response Th1-type. This response is marked by interleukin (IL)-12 production by antigen presenting cells, and interferon-gamma (IFN-γ) production by CD4+ T cells, CD8+ T cells, and natural killer (NK) cells (**Figure 1**). The Th1-type reaction most often induces a local inflammatory reaction, hence the interest of activating a Th2-type immune reaction that inhibits the activation of the Th1 immune response. The Th2 response is mediated primarily by two interleukins IL-4 and IL-10 [6] (**Figure 1**). This immune regulation seems to be of great interest in reducing the inflammatory reactions responsible for most lesions, but it makes the soil favorable to parasite multiplication. Despite the immune responses against *T. gondii*, this parasite has the ability to escape and spread via the bloodstream to infect different organs. In the central nervous system, tachyzoites have the ability to cross the blood-brain barrier (BBB), infect different types of nerve cells, and become encysted bradyzoites that persist throughout the life of the host. Several studies have shown in the mouse model the importance of IFN-γ in this control [9]. Among the parasitic factors, the genotype also has a role in the influence of the evolution of *Toxoplasma* infection. Type I strains are associated with high virulence in mice, whereas type II or III strains are considered avirulent for mice. Type I tachyzoites have the ability to cross epithelial barriers and reach immune-privileged sites more rapidly than type II

**Figure 1.**

*Diagram showing the cerebral immune response during a cerebral toxoplasmosis infection in mice.*

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Toxoplasma *Immunomodulation Related to Neuropsychiatric Diseases*

strains [10]. In human, several studies have reported severe acquired toxoplasmosis due to atypical strains in immunocompetent individuals. An overrepresentation of other atypical strains has been observed in patients with ocular toxoplasmosis [11]. The influence of the parasite strain on the development of the infection or the

The central nervous system is closely linked to the immune system at several levels. The cerebral parenchyma is separated from the periphery by the BBB, the integrity of which is maintained by tight endothelial junctions. This barrier under normal conditions prevents the entry of mediators such as activated leukocytes, antibodies, complement factors, and cytokines. The myeloid cell line plays a crucial role in the development of immune responses at the central level, it includes two main subtypes: microglial cells, distributed in the cerebral parenchyma; perivascular macrophages located in the capillaries of the basal lamina brain and the choroid plexus. In addition, astrocytes, oligodendrocytes, endothelial cells, and neurons are also involved in the immune response in the CNS. By modulating synaptogenesis, microglial cells are more particularly involved in the restoration of neuronal connectivity following inflammation. These cells release immune mediators, such as cytokines, that modulate synaptic transmission and alter the morphology of dendritic spines during the inflammatory process after injury. Thus, the expression and release of immune mediators in the cerebral parenchyma are closely related to the plastic morphophysiological changes in the dendritic spines of neurons. Based on these data, it has been proposed that these immune mediators are also involved in the learning and memory processes. Microvasculature is a key element of brain damage. Endothelial cells are an important source of immune mediators such as a nitric oxide (NO), which are involved in the process of immune cell adhesion [12, 13]. A recent study shows that *T. gondii* invasion of neural tissue is mediated by epidermal growth factor receptor (EGFR), enhancing invasion likely by promoting survival of the parasite within endothelial cells [14]. Damage to the BBB can lead to increased permeability, which facilitates leucocyte access to the brain parenchyma. The release of mediators of endogenous inflammation and neurotoxins and the promotion of phagocytosis of cellular debris [6, 14]. Excessively activated microglial cells can cause major histocompatibility complex class II (MHCII) expression. This molecule facilitates the involvement of these cells in immune responses. Activation of microglial cells strongly influences the profile of cytokines released by two distinct mechanisms: recognition receptors and activation of the immune response [13, 15]. Activation of monocytes and macrophages is an important part of the innate immune response; it induces the production of proinflammatory cytokines and chemokines such as IL-8, monocyte chemoattractant protein1 (MCP-1), macrophage inflammatory proteins (MIP-1α and MIP-1β). Regulatory cytokines can also be activated within the CNS, such as IL-4 and IL-10 [8]. Expression of MHCII and adhesion molecules (CD11a, CD40, CD54, CD80, CD86) in activated microglial cells indicates that these cells can acquire antigen presenting activity and participate in the activation of T cells [16]. This suggests the existence of a network of complex interactions linking microglial cells, astrocytes and T cells; which creates a balance between the Th1/Th2 signals, which defines the immune response of the CNS. The role of astrocytes in the CNS is even more complex than that of microglial cells. Astrocytes are divided into two main subtypes: fibrous astrocytes located in the white matter; protoplasmic astrocytes located in the gray matter. These contribute to

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

cerebral pathology remains however unknown.

**2.1 The central nervous system immunity**

**2. The cerebral anti-***Toxoplasma* **immune reaction**

strains [10]. In human, several studies have reported severe acquired toxoplasmosis due to atypical strains in immunocompetent individuals. An overrepresentation of other atypical strains has been observed in patients with ocular toxoplasmosis [11]. The influence of the parasite strain on the development of the infection or the cerebral pathology remains however unknown.
