**5. Critical roles of astrocytes in toxoplasmic encephalitis**

Astrocytes exert considerable effort to maintain control over *T. gondii*. Although the expression of gamma interferon (IFN-y) has been proven to significantly regulate *T. gondii* in the brain, the molecular mechanism behind these protective actions is not well known. A comprehensive analysis revealed that IFN-gamma-induced GTPase (IGTP) suppressed the replication of *T. gondii* tachyzoites in astrocytes. Therefore, IGTP protects TE *via* astrocyte-mediated mechanisms [55]. However, it has been established that the signal transducer and activator of transcription 1 are required for IFN-gamma to suppress parasite multiplication in astrocytes (STAT1). Experimentally, it has been shown that in animals devoid of STAT1 expression, astrocytes cannot suppress *T. gondii* replication and, thus, cannot prevent neuropathology [56]. It has been shown that the orphan nuclear receptor regulates STAT1 signaling and host defense in astrocytes. In TE, astrocytes play a crucial role in developing a robust resistance to the parasite and complicated molecular pathogenesis [57]. It has been discovered that astrocytes' glycoprotein 130 (gp130) expression plays a crucial

role in mice with the experimental TE model. An experiment with animals lacking gp130 showed that apoptosis in astrocytes increased, and inflammatory lesions could not be avoided. However, it has been shown that gp130 expression by astrocytes is not required for *T. gondii* regulation in these cells. In summary, it has been shown that astrocyte-expressed gp130 alleviates neuropathology but does not prevent parasite replication [58].

The importance of astrocytes in the immunopathogenesis of TE cannot be overstated. Astrocytes are among the cells infected by tachyzoites in both *in vivo* and *in vitro* experiments. *In vivo* investigations have shown that tachyzoites target and infect astrocytes after invading the brain. Activated astrocytes have been demonstrated to decrease parasite multiplication in TE and, as a result, help alleviate severe neuropathology such as necrosis [59–63]. Mice have been demonstrated to have little chance of surviving in TE, which was established in mice whose glial fibrillary acidic protein (GFAP) expressions were suppressed, and astrocyte numbers were lowered in an experiment [58]. This condition may be described as follows: in mice without a protective astrocyte population, the efficiency of GFAP, an essential immunoregulatory, would be reduced. As a result, parasite replication rises, and because of this replication, more widespread and severe inflammatory lesions develop, resulting in increased neuropathology severity [58, 64]. Severe GFAP expressions from astrocytes were identified in a potential tissue cyst reactivation. This robust expression shows that astrocytes exert effort to prevent neuropathology in the neuroparenchyma. Therefore, it has been shown that astrocytes function as immunomodulatory and immune effector cells in TE [28].

It has been revealed that astrocytic transforming growth factor-beta (TGF-β) signaling is crucial for suppressing the neuroinflammatory response in TE. It has been shown that inhibiting astrocytic TGF- β signaling increases immune cell infiltration into the brain, resulting in severe neuronal damage. Inhibiting astrocytic TGF-β signaling has no effect on CNS parasite burden in acute or chronic phases, suggesting a separate molecular mechanism in astrocytic TGF-β-mediated neuroinflammation. Astrocytic TGF-β signaling has a role in avoiding neuronal tissue damage in TE *via* astrocytic TGF-β signaling [65].

*T. gondii*-infected astrocytes have been shown to express prostaglandin E2 (PGE2). PGE2 production by infected astrocytes has also been linked to microglia IL-10 expression reliant on cyclic adenosine monophosphate (cAMP). Finally, *T. gondii*infected astrocytes suppress NO generation by IFN-gamma-activated microglia, and cAMP-dependent IL-10 expression by microglia contributes to neuropathology reduction (**Figure 7**) [66].

### **6.** *T. gondii* **and schizophrenia: Pathogenesis relationship**

The relationship between *T. gondii* and schizophrenia has been investigated for decades. However, despite such studies and extensive meta-analyses, the relationship between the two diseases remains obscure. Because it is a current topic, this is regarded as a significant point. Kynurenic acid (KYNA), a metabolite of the kynurenine pathway derived from the breakdown of tryptophan, is synthesized by astrocytes [67–69]. In the pathogenesis of schizophrenia, impaired metabolism of the brain kynurenine pathway (KP) and consequently elevated kynurenate levels have been conclusively demonstrated [70]. In response to intense glial activation during TE, KYNA formation increases substantially. To summarize,

*Neuroimmunopathology in Toxoplasmic Encephalitis DOI: http://dx.doi.org/10.5772/intechopen.109341*

KP metabolites play an essential role in the pathogenesis of *T. gondii*-mediated schizophrenia (**Figure 8**) [71].

The Matrix Metalloproteinase-9 (MMP-9) gene has been extensively studied in schizophrenia, and it has been demonstrated that the MMP-9 gene polymorphism may play a role in the pathogenesis of schizophrenia [72–74]. In TE, tachyzoiteinfected astroglial cells increase the expression of Matrix Metallopeptidase-2 and -9 (MMP-2 and MMP-9). It has even been reported that the inflammatory development of encephalitis can be controlled by inhibiting MMP-2 and MMP-9 expression [75], because MMP-2 and MMP-9 expressed by astroglial cells have been shown to contribute to extracellular matrix degradation in brain tissue [76]. These findings show that MMP expression is essential in the pathogenesis of *T. gondii*-mediated schizophrenia (**Figure 9**).

The similarities between the pathogenesis of schizophrenia and TE are quite striking. There is an increase in NO production in schizophrenia [77] and neuropathology associated with OS [78, 79]. However, it has been demonstrated that the antioxidant enzyme SOD in the brain is significantly decreased in schizophrenia [80]. A considerable drop in the expression of the anti-apoptotic protein Bcl-2 has been discovered in the pathogenesis of schizophrenia [81], and apoptosis has been proven to play a crucial part in the process [82–84]. Similarly, cytokine-mediated neuronal damage has been documented in schizophrenia, and declines in the number and density of neurons have been reported [85]. When examining the pathogenesis of TE considering these data, it has been discovered that there are remarkable similarities, and their link is highlighted. Pathological levels of eNOS, iNOS, and nNOS-derived NO production have been observed in TE [28]. Moreover, it was shown that OS increased while SOD activity reduced considerably [27]. In addition, severe inhibition of the expression of Bcl-xL, an antiapoptotic protein, and triggering of apoptosis have been clearly demonstrated in TE models [26]. In TE, elevated GMF expressions, which induce proinflammatory responses in glial cells, revealed cytokine-mediated neuropathology [53] (**Figure 10**).

#### **Figure 8.**

*T. gondii-mediated KYNA elevation and its association with schizophrenia.*

In a broad sense, the parallels between the pathogenesis of these diseases are highly remarkable. It also shows their close relationship. These investigations show the molecular mechanism behind the pathogenesis of schizophrenia mediated by *T. gondii*.

#### **7. Neurohistopathological findings of toxoplasmic encephalitis**

Nonsuppurative and/or necrotizing meningoencephalitis are among the fundamental histological findings in TE. The existence of tissue cysts is a crucial observation. It has been shown that tissue cysts may be found throughout the brain, with the increased density in the cerebral cortex, hippocampus, thalamus, and amygdala regions being a noteworthy histopathological finding. The histological findings are neuronal degeneration and necrosis, localized gliosis foci, hyperemia,

*Roles of MMP-2 and MMP-9 in TE neuropathology and schizophrenia.*

**Figure 10.**

*The reason why TE continues to be a major health issue.*

perivascular mononuclear cell infiltration, and capillary endothelial hypertrophy. As shown earlier, Purkinje cells are very susceptible to *T. gondii* tachyzoites. Histopathologically, these cells are also shrunken, with eosinophilic cytoplasm and necrotic [26–28, 86–88].
