**4. Molecular mechanism of neuropathology caused by** *T. gondii*

Tachyzoites that reach the brain parenchyma after improved strategies have crossed the BBB may induce severe neuropathology and host mortality. Although the molecular pathways of neuropathology are continuously investigated, there are still several unanswered questions. Chemokine (C–C motif) receptor 2 (CCR2), a crucial chemokine receptor with a microbicidal function, has a tight relationship with the parasite burden in the brain. In mice whose CCR2 receptor was experimentally blocked, the immune system cells in the brain were markedly inactive, resulting in a considerable increase in the parasite load in the brain [32]. In conclusion, the CCR2 receptor is necessary to regulate parasite replication in peripheral organs and the CNS in particular (**Figure 3**). Although the deadly TE produced by the reactivation of latent tissue cysts in the brain has been investigated for many years, the molecular mechanism of reactivation is still unknown.

**Figure 3.** *The role of CCR2 in TE.*

The significance of nitric oxide (NO) generation in chronic TE is remarkable since it must be in a delicate balance. This section focuses on two distinct topics. The first is NO's neuroprotective impact, while the second is its neurotoxic and neuropathological consequences, which may be severe. During *T. gondii* infection, nuclear factor kappa B and inflammatory cytokines are overexpressed in blood-derived macrophages. IL-1α was overexpressed in microglia and IL-1β in macrophages during infection compared with control groups. In TE, IL-1R1, gasdermin-D-dependent IL-1α, and caspase-1/11 have been demonstrated to control parasite multiplication, limit neuroinflammation, and regulate immune cell multiplication infiltration [33]. This research shows that alarmin IL-1α, produced by microglia, works hard to reduce the neuropathology found in TE (**Figure 4**).

The anti-parasitic action of NO is diminished in C57BL/6 mice vulnerable to chronically infected *T. gondii*, and TE, which leads to mortality, occurs because of the reactivation of tissue cysts [34–38]. NO plays a significant role in the shift from acute to chronic infection. There have been investigations into the critical functions of NO in the shift from acute to chronic infection. In a nutshell, NO causes the conversion

**Figure 4.** *IL-1R1 and Caspase 1/11-mediated pathway for TE attenuation.*

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

of tachyzoite to bradyzoite forms and attempts to regulate the course of the illness [34–36, 38–43]. It has been shown that a reduction in inducible nitric oxide synthase (iNOS) expression is linked to tissue cyst reactivation [34, 37, 38]. However, the focus of this section will be on the occurrence of neuropathology induced by NO generated over physiological limitations, because it has been proven that NO causes significant neuropathology rather than having neuroprotective characteristics. Despite the emphasis on the consequences of iNOS-derived NO generation in TE, it was shown that NO was not only iNOS-derived. Endothelial nitric oxide synthase (eNOS) derived NO produced from endothelial cells infected with tachyzoites, and neuronal nitric oxide synthase (nNOS)-derived NO expressed by neurons also induces neuropathology at an unavoidable level [28]. It has been shown that all NO sources play a part in disease pathogenesis, explaining why the NS has progressed to such a severe level (**Figure 5**).

Apoptosis causes neuropathology found in TE, as shown by high caspase 3 expression and suppression of B-cell lymphoma-extra-large (Bcl-xL) expression, which has anti-apoptotic characteristics. The observed apoptosis is driven both extrinsically by the expression of Tumor necrosis factor receptor 1 and caspase 8 and internally by the production of caspase 9, which is a component of the apoptosome complex. *T. gondii* inhibiting Bcl-xL is exceptionally notable. The most surprising discovery in this research is that Purkinje cells were susceptible to intrinsically caused apoptosis. Thus, intrinsically caused apoptosis has been identified as one reason for Purkinje cell death in TE patients [26]. Pathological neurofilament (NF) accumulation in neurodegenerative cerebral diseases, particularly in injured neurons, is the most fundamental sign of acute neuroparenchymal destruction [44–46]. The critical element to understand in this section is that NF accumulates to pathological levels during the acute stage. TE had a large amount of

**Figure 5.** *The role of iNOS in TE survival.*

NF buildup in the chronic TE stage. The occurrence of degeneration and necrosis in acute neuroparenchymal structures owing to tissue cyst reactivation was the cause. As a result, it has been shown that monitoring NF accumulations may evaluate and track neuropathology in acute TE. Consequently, it has been demonstrated that the degree of neuropathology in acute TE may be identified and tracked by monitoring NF accumulations [28]. In experimental models of ischemia in rats, neuron-specific enolase (NSE) may be employed as a quantifiable marker to determine the degree of neuronal injury [47]. NSE is a good-quality marker for assessing TE-related neuropathology's severity and disease follow-up. NSE strongly showed the severity of *T. gondii*-mediated neurodegenerations in neuroparenchymal structures [27]. This is a significant result because, given the absence of a successful therapy for TE that has yet to be addressed entirely, it will play an essential role in assessing neuroprotective drugs.

It is widely established that oxidative stress (OS) plays a significant part in the molecular process of neurodegeneration/neuropathology in TE. Glutathione reductase and 8-hydroxy-2′-deoxyguanosine have been expressed at pathological levels in TE, and the expression of Cu/Zn superoxide dismutase (SOD), a critical endogenous enzymatic antioxidant that protects cells against OS-related apoptosis, is similarly hindered. Therefore, OS and n/mt DNA damage produced by OS shows severe neuropathology mediated by *T. gondii*, because a reduction in antioxidant enzyme activity provides crucial insight into the neuropathogenesis of TE [27]. Glia maturation factor (GMF)-mediated proinflammatory responses have been found to play a crucial role in the neuropathogenesis of neurodegenerative and demyelinating diseases and produce severe neuropathology [48–51]. In addition, it has been shown that elevated GMF expressions play a crucial role in the neuropathogenesis of Alzheimer's disease, a severe neurodegenerative disorder [48, 52]. Dincel's 2017 research found abnormal levels of GMF-b expression, a severe proinflammatory cytokine, in reactive glial cells and specifically in gliosis foci in the brain tissues of animals. This research showed a relationship between GMF overexpression in glial cells in TE and neuronal damage. It has been explained that the subsequent neurotoxicity is GMF-mediated neuropathology that has not been documented in TE before [53]. Uncovering a novel GMFmediated proinflammatory mechanism is a significant step forward to our knowledge of neuropathogenesis.

The pathogenesis of TE has been linked to an enhanced unfolded protein response and extended ER stress. In the model created with *T. gondii*, type I strains showed that Rhoptry protein 18 (ROP18) is associated with the N-terminal portion of endoplasmic reticulum (ER)-associated protein called reticulon 1-C (RTN1-C), an ER protein expressed in the CNS [54]. As a result of ROP18 phosphorylation of RTN1-C, it has been explained that it triggers ER-stress-mediated apoptosis in neuronal cells. In addition to these findings, it has been demonstrated that ROP18 phosphorylation of RTN1-C increases glucose-regulated protein 78 acetylation by decreasing the activity of histone deacetylase. These results have been associated with neuronal apoptosis [54]. These findings clearly show that ER stress and ROP18 expression play critical roles in the pathogenesis of TE, and treatment modalities should focus on this target (**Figure 6**).

The neuropathology found in TE is critical. Although the neuropathology associated with chronic toxoplasmosis is thought to be resolved, we should not ignore their neuropsychiatric consequences. Any reactivation of tissue cysts intimately linked to the immune system might end in mortality. Although the aim here is to reduce neuropathology and avoid permanent damage, we should not ignore that the goal is

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

**Figure 6.**

*Mechanism underlying the significant apoptosis seen in TE.*

to eliminate tissue cysts. Because as long as the existence of tissue cysts in the brain persists, patients cannot avoid the risk of death.
