In vitro experiments show that the infection of human cervical carcinoma epithelial cells (HeLa) and human preputial fibroblasts (HFFs) with the T. gondii RH strain induces the expression and secretion of the proinflammatory chemokine IL-8 (CXCL8), growth-related carcinogens α (GROα/CXCL1) and MCP-1 (CCL2) (Denney et al., 1999). These chemokines are required for the recruitment of lymphocytes and monocytes to the CNS. Similarly, an in vivo study demonstrates that CNS ECs are important producers of proinflammatory chemokines, including CCL2, CCL5/RANTES, and CXCL10/CRG-2/IP-10, and these chemokines are key in promoting the migration of effector macrophages to the brain to combat the parasitic invasion (Daneman and Prat, 2015).

In addition to ECs, T. gondii infection induces the production of chemokines CXCL9/MuMIG in microglia, which promote the activation and chemotactic activity of T cells, monocytes, and macrophages (Ochiai et al., 2015). CXCL10 is also expressed by astrocytes in response to the infection (Strack et al., 2002). CXCL10 is a chemokine vital for the recruitment of CD8+ T cells to the CNS, and the inhibition of CXCL10 leads to an increased parasitic burden in the CNS (Khan et al., 2000). A recent study shows that IL-33 signaling targets astrocytes via the ST2 receptor, leading to the production of inflammatory chemokines such as CCL2 and CXCL10 (Still et al., 2020).

CCR5, a high-affinity receptor for CCL5, provides a primary signal for CD8α subsets of dendritic cells (DCs) to induce IL-12 synthesis to establish IFN-γ-dependent T. gondii resistance (Aliberti et al., 2000). Defective expression of CCR5 may disrupt the recruitment of CCL5, Th1 cells and macrophage inflammatory proteins 1α and 1β (MIP-1α/CCL3 and MIP-1β/CCL4) (Brenier-Pinchart et al., 2001). Similarly, CCR2 is essential for the activation of bactericidal mediators needed to control T. gondii replication in the CNS: CCR2-deficient mice have an increased susceptibility to ME49, while parasite replication in the CNS is not inhibited (Benevides et al., 2008). During chronic infection of T. gondii ME49 strain, CXCL9, CXCL10 and CCL5 are expressed in the brains of mice (Wen et al., 2010).

Peripheral blood monocytes and DCs migrate to the site of inflammation in response to cytochemokines. They undergo roll, attach, and trans-endothelial migrate (TEM) under the guidance of various adhesion molecules on the surface of ECs. T. gondii infection induces ICAM-1 expression in DCs and ECs, and thereby enhances TEM frequency (Ross et al., 2022; Yang et al., 2019).

In addition, T. gondii infection promotes integrin-CAM-dependent movement of DCs to ECs (Ross et al., 2021). Previous studies have shown that IFN-γ induces the expression of VCAM-1 on ECs, which in turn binds to integrin α4β1 on CD8+ T cells, facilitating the recruitment of T cells into the brain (Wang et al., 2007). Toxoplasma gondii can disrupt integrin β1 signaling and its localization on the cell membrane, thereby altering the migratory behavior of parasitic leukocytes (Cook et al., 2018). Another study suggests that the expression of integrin αvβ3 by Raw 264.7 cells serves as the basis for T. gondii crossing the BBB. This integrin is able to regulate the binding of integrin α2β1 with fibronectin and the conversion of preαv to the mature αv subunit, a process that involves the membrane type 1 matrix metalloproteinase (MT1-MMP) signaling pathway (Seipel et al., 2010). In contrast, the level of MT1-MMP is elevated on the surface of macrophages infected by T. gondii. MT1-MMP promotes the degradation of EC extracellular matrix (ECM) and thus promote the TEM of the infected macrophages (Seipel et al., 2010). Therefore, this pathway may be the preferred way for the processing of the integrin prosubunit in T. gondii-infected macrophages (Seipel et al., 2010). In addition, human ICAM-1 can interact with parasite adhesin MIC2 on the surface of T. gondii and directly facilitates T. gondii adhesion (Barragan et al., 2005).

The integrity of the ECM another important component of the BBB, also plays a crucial role in preventing invasion by pathogens. During T. gondii infection, MMPs degrade the ECM and promote the infiltration of T cells into the brain. However, this process can be partially inhibited by tissue metalloproteinase inhibitors (TIMPs) (Suzuki et al., 2011). The regulation of MMP activity and TIMP-1 induction in astrocytes is mediated by the NF-κB signaling pathway (Harris et al., 2007). However, T. gondii infection hinders the activation of the NF-κB signaling pathway in astrocytes (Mason et al., 2004). TIMPs in the CNS can effectively decrease cerebral microvascular permeability and maintain BBB integrity by inhibiting MMP activity (Chen et al., 2013). In the context of T. gondii infection, macrophages may penetrate the BBB by promoting the degradation of fibronectin, laminin and type IV collagen, thereby acting as a “Trojan horse” (Da Gama et al., 2004). Further, T. gondii infection lead to an upregulation of MMP-8 and MMP-10 by T cells and CNS resident astrocytes. Therefore, to prevent the migration of T. gondii to the immune isolation site and evade host immunity, one strategy is to inhibit MMPs activity by enhancing the expression of TIMPs (Clark et al., 2011).

Toxoplasma gondii can interact with TJP occludin in intestinal epithelial cells, and it can also disrupt the integrity of the tight junction proteins (TJPs) in retinal pigment epithelial cells (ARPE-19), resulting in increased intercellular permeability and disruption of barrier function (Nogueira et al., 2016; Weight et al., 2015). Although ECs and their TJs constitute the primary barrier that the parasite must traverse to breach the BBB (Masocha and Kristensson, 2012), there are still limited researches on the effect of T. gondii on TJPs within BBB ECs. Deletion of the TJP regulator focal adhesion kinase (FAK), also known as protein tyrosine kinase 2 (PTK2), in ECs increases BBB permeability and accordingly elevates the T. gondii load in the brain parenchyma (Olivera et al., 2021). FAK is involved in regulating EC adhesion and FAK complex signaling pathways to maintain BBB integrity (Lee et al., 2010). Interestingly, T. gondii infection has been reported to inactivate FAK function, thereby transiently disrupting the stability of intercellular TJPs and promoting their intercellular migration (Ross et al., 2019). T. gondii infection also leads to an elevation in mRNA and protein levels of brain complement 1q (C1q), which helps clear T. gondii from the CNS, but also results in neurodegeneration by degrading neuron connections and synapse loss (Xiao et al., 2016). Additionally, T. gondii infection upregulates complement component 3 (C3), further disrupting TJs in the CNS (Huang et al., 2019). Collectively, these effects promote the traversal of T. gondii across the BBB through a paracellular migration pathway.

Toxoplasma gondii can induce the activation of microglia, upregulate the expression of proinflammatory cytokines, and mediate neuronal death in TE (Figure 1). Therefore, inhibiting the activation of microglia may be a new therapeutic strategy for TE (Zhang et al., 2014). Activated microglia cluster at sites of neurodegenerative changes, enveloping or surrounding degenerating neurons, which are the pathogenesis between chronic T. gondii infection and neuropsychiatric disorders (Li et al., 2019). After T. gondii colonizes the brain, adherence of leucocytes increases, accompanied by increased reactivity of microglia and microglial hypertrophy (Estato et al., 2018). Previous studies have shown that chronic T. gondii infection leads to the interaction of CX3CL1, complement and microglia, ultimately promoting phagocytosis of microglia and clearance of degenerative neurons in the cerebral cortex (Li et al., 2019).

A recent study suggests that the IFN-γ-STAT1 signaling pathway participates in microglial activation after T. gondii invades the CNS to clear the parasite through immune-associated GTase (IRG) and guanylate binding protein (GBP) activity (Cowan et al., 2022). Microglia can also activate ECs in the CNS to release the proinflammatory cytokine IL-1α (Batista et al., 2020), upregulating the expression of ICAM and VCAM in ECs.

Inflammatory damage caused by invading pathogens can trigger the production of proinflammatory mediators, such as Toll-like receptor 2 (TLR-2) expressed by microglia, as well as promote the expression of protein kinase C and inducible nitric oxide synthase (iNOS). These pathways contribute to the phagocytic activity of microglia against pathogens (Domínguez-Punaro Mde et al., 2010). In addition, T. gondii infection can also lead to sustained upregulation of complement factors B and C5a receptors in the mouse brain through the activation of microglia (Shinjyo et al., 2020). However, studies have also shown that the invasion of IFN-γ-activated microglia by T. gondii can inhibit the production of iNOS and transforming growth factor-β1 (TGF-β1) and in turn inhibit the proinflammatory effects of activated microglia and prevent neurodegeneration (Rozenfeld et al., 2005).

Astrocytes are the most abundant glial cells in the CNS, play a crucial role on the growth, development and functional maintenance of neurons as neurotrophic factors. They participate in the release of neurotransmitters to maintain the survival and communication of neurons. Additionally, they are also an important part of the BBB that regulates the permeability of the microvasculature in the CNS (Abbott et al., 2006).

Although T. gondii can infect multiple types of cells within the CNS, including astrocytes, microglia, vascular ECs and neurons, in the early stages of tachyzoite invasion, astrocytes show a higher proportion of infection (Gonzalez et al., 2007). After infection with T. gondii, the astrocyte-specific marker glial fibrillary acidic protein (GFAP) level, is upregulated, showing widespread astrocyte activation (Nasuhidehnavi and Yap, 2021). Activated astrocytes promote the production of cytokines (including IFN-γ and chemokines), presentation of antigens, and expression of costimulatory molecules (Wilson and Hunter, 2004). Activation of astrocytes caused by T. gondii infection is one of the hallmarks of TE, and activated astrocytes in turn can inhibit the replication of T. gondii within the brain (Halonen et al., 1998).

Activation of astrocytes by T. gondii triggers the release of IL-1α, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF), driving local anti-toxoplasma inflammatory responses in the brain (Fischer et al., 1997). In vivo and in vitro experiments demonstrate that the ability of IFN-γ to inhibit T. gondii replication in astrocytes is dependent on signal transducers and transcriptional activator 1 (STAT1), this inhibition is not observed in mice lacking STAT1 specifically in astrocytes (Hidano et al., 2016). In addition, the soluble factor prostaglandin E2 (PGE2), released by infected astrocytes, can inhibit the production of nitric oxide by IFN-γ-activated microglia, thereby preventing neuronal degeneration (Rozenfeld et al., 2003).

The expression and release of cytokines and chemokines from astrocytes depends on the involvement of Toll-like receptors (TLRs) and specific TLR-binding ligands (Krasowska-Zoladek et al., 2007). TLR is a germline-encoded pattern recognition receptor (PRR) essential for host cell recognition of intracellular parasites, as well as microbial pathogens (Kawai and Akira, 2011). Studies have shown that TLR is involved in interactions between glial cells and neurons, as well as between immune cells and innate cells of the CNS (Kawai and Akira, 2010). TLR-11, a toxoplasma-specific receptor, plays a central role in immune recognition against T. gondii infection and is expressed in astrocytes, neurons, and microglia/blood-derived macrophages in the brains of infected mice (Atmaca et al., 2014). Human TLR-5, evolutionarily similar to mouse TLR-11, mediates T. gondii actin-binding protein-induced proinflammatory responses in human monocytes (Salazar Gonzalez et al., 2014). TLR-9 mediates distinct inflammatory changes in intestinal and extraintestinal compartments, including the brain (Bereswill et al., 2014). TLR-2 also responds to T. gondii infection by participating in the production of CCL2 and TNF. Astrocytes TLR-2 and TLR-4 are involved in the expression and release of IL-1, IL-6, TNF, C-C, or C-X-C chemokines (Bsibsi et al., 2007). In contrast, TLR3 in astrocytes induces the expression of neuroprotective factors and anti-inflammatory cytokines (Liu et al., 2020). Interestingly, treatment with an astrocyte TLR-9 antagonist, oligodeoxynucleotide 2088 (ODN 2088), increased the release of CCL1, thereby promoting the chemotaxis of pericardial macrophages in astroglia-macrophage coculture (Li et al., 2020). Additionally, this antagonist can alter the signaling between astrocytes and macrophages, promoting the polarization of peripheral macrophages toward an M2 phenotype (Li et al., 2020). Moreover, neuron-expressed TLR induces the expression of proinflammatory factors such as IFN-γ and cytokines and can participate in neuronal cell death through apoptosis (Adhikarla et al., 2021). However, the astrocyte TGF-β signaling pathway limits inflammatory responses and reduces neuronal damage during T. gondii infection in the CNS (Cekanaviciute et al., 2014). In addition to cytokines and chemokines, MMP-2 and MMP-9 produced by SVG p12 astrocytes line degrade fibronectin, leading to degradation of the BBB extracellular matrix (Lu and Lai, 2013a). NF-κB is involved in regulating the expression of MMP-2 and MMP-9 in T. gondii-infected astrocytes, so inhibiting the Erk1/2-NF-κB signaling pathway in astrocytes may represent a potential approach for controlling the development of inflammation in TE (Lu and Lai, 2013b). Additionally, the expression of gp130, a signaling subunit shared by IL-6 family receptors, has been reported to inhibit apoptosis in T. gondii-infected astrocytes in mice, which helps control the spread of tachyzoites in the brain (Drögemüller et al., 2008). In summary, invasion of the CNS by T. gondii activates host astrocytes to produce various inflammatory factors, which promote the recruitment of macrophages and lymphocytes to the brain and act as antigen-presenting cells expressing costimulatory molecules (Figure 1).

Neurons are the main target cells infected by T. gondii within the CNS (Cabral et al., 2016). In contrast to microglia and astrocytes, the parasite can establish persistent infections in neurons, which may be due to the parasite’s directly regulation on neurons. As the infection progresses, Toxoplasma cysts in neurons enlarge, their walls thicken, and they assume a rounder shape, all maintaining the integrity of the neuronal cell membrane and concurrently inhibiting neuronal activity (Haroon et al., 2012). Notably, during the chronic phase of T. gondii infection in the CNS, the rupture of these cyst walls is a frequent occurrence, allowing bradyzoites to escape and subsequently infect adjacent components of the neuronal vascular unit (NVU) (Hermes et al., 2008).

Studies have shown that T. gondii infection in neurons can induce the production of IL-6, TGF-β1, MIP-1α, MIP-1β and other neuronal cytokines and chemokines (Figure 1), which are involved in the immune response against T. gondii in the brain immune defenses (Schlüter et al., 2001). Similar to astrocytes, the expression of neuronal gp130 is critical for preventing neuronal loss, excessive inflammation, and lethal processes in TE in mice (Händel et al., 2012). A recent discovery has highlighted that exogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) can inhibit the expression of proinflammatory cytokines such as IFN-γ, IL-6, iNOS and IL-1β and alleviate neuronal injury by increasing the expression of brain-derived neurotrophic factor (BDNF) (Figueiredo et al., 2022).

Alzheimer’s disease (AD) is a prevalent degenerative disease of the CNS characterized by progressive memory loss, cognitive decline, and various neuropsychiatric symptoms and behavioral disorders (Nayeri et al., 2021). It is well known that neuroinflammation-induced neuronal degeneration plays a key role in the pathogenesis of chronic neurodegenerative diseases. A large number of studies have shown that there are many inflammatory markers in the brains of AD patients, including an increase in inflammatory cytokines and chemokines and the accumulation of activated microglia in damaged areas (Torres et al., 2018).

The hallmark of AD pathology involves extensive deposits of beta-amyloid protein (Aβ) forming amyloid plaques in the brain, leading to significant neuronal damage (Lee et al., 2010). After T. gondii infection, the amyloid precursor protein (APP) in host’s CNS is abnormally cleaved, and its expression level drops, resulting in a large amount of Aβ deposition in brain tissue (Figure 2A). Acetylcholine (ACh), an essential neurotransmitter implicated in AD, when rapidly hydrolyzed by acetylcholinesterase (AChE) into acetate and choline, leads to deficits in learning, memory, and cognition (Ferreira-Vieira et al., 2016). T. gondii infection results in high AChE release and lower ACh levels, leading to learning and memory impairment in the infected host (Nayeri et al., 2021). Another important pathological change in AD is the hyperphosphorylation of tau protein, which leads to neurofibrillary tangles, structural changes in neuronal cytoskeletal proteins, and ultimately neuronal death. T. gondii infection leads to tau phosphorylation by activating glycogen synthase kinase 3β (GSK3β), leading to significant apoptosis of hippocampal neurons (Tao et al., 2020). In addition, the anxiety-like behavior induced by T. gondii infection in mice may be related to reduced N-methyl-D-aspartate receptor (NMDAR) expression and loss of olfactory sensory neurons (Torres et al., 2018).

Interestingly, chronic T. gondii infection can improve Aβ deposition in AD by activating the immune system, mainly by recruiting monocytes, enhancing monocytic phagocytosis and promoting soluble Aβ degradation; the excessive activation of glial cells by T. gondii may lead to Aβ degradation (Möhle et al., 2016). Replicating this phenomenon in animal models with varying infection levels could deepen our understanding of the relationship between T. gondii and brain disorders, presenting new avenues for research into treatments for conditions like AD.

In addition, the specific mechanism of how T. gondii infection affects AChE release is still unclear. Previous studies have shown that T. gondii infection can increase the levels of AChE in the brains of mice (Tonin et al., 2014), and research on improving AD pathology by targeting T. gondii infection may have significant research implications.

Schizophrenia is a chronic long-term mental disorder characterized by a progressive deterioration in sensory, cognitive, emotional, and behavioral functions (Tandon et al., 2013). Risk factors such as childhood trauma, obstetric complications, drug abuse, and neuroinflammation caused by infection can all contribute to the development of schizophrenia (Radhakrishnan et al., 2017; Stilo and Murray, 2019). At present, most studies use serum anti-T. gondii IgG as an indicator of T. gondii infection, and the serum positivity rate of Toxoplasma IgG in schizophrenia patients is significantly higher than that in the control group (Oncu-Oner and Can, 2022). A meta-analysis showed that the serum positivity rate of T. gondii in schizophrenic patients was 2.73 times higher than that in the general population (95% confidence interval, 2.10–3.60; p < 0.000001) (Torrey et al., 2007), suggesting a moderate to strong association between T. gondii infection and schizophrenia, and raising the possibility that T. gondii infection could contribute to the development of this mental disorder (Kezai et al., 2020). Chronic infection with T. gondii may cause neuroinflammation, which in turn can lead to neurotransmitter imbalances and subsequent psychopathological symptoms, potentially exacerbating the progression of schizophrenia.

An important factor in schizophrenia is the dysregulation of dopamine (DA), a neurotransmitter whose elevated levels are implicated in the disease (Willner, 1997). There is an association between DA and T. gondii infection and schizophrenia, and it is associated with an increase in the hippocampus and other specific regions (Skallová et al., 2006). In T. gondii infected mouse models, abnormal elevation in DA concentration in the synaptic cleft of neurons lead to schizophrenia (Yin et al., 2022). The upregulation of tyrosine hydroxylase (TH) expression in the infected host brain may be related to TgAaaH1 and TgAaaH2, which encode TH in the Toxoplasma genome, leading to excessive production of DA in infected nerve cells (Gaskell et al., 2009). An increase in DA concentration was also detected in cysts and surrounding tissues in patients with schizophrenia (Flegr, 2015).

The increase in kynurenine (Kyn) metabolites is closely related to the onset of schizophrenia (Zhou et al., 2022). Studies have found that T. gondii infection may lead to an increase in 3-hydroxykynurenine (3-HK, metabolites of Kyn), quinolinic acid (QUIN) and kynurenic acid (KYNA) in the brain through activating microglia and astrocytes (Figure 2B). The synthesis of KYNA is initiated by starting the oxidative cycle of tryptophan through indoleamine 2,3-dioxygenase (IDO) and/or tryptophan dioxygenase (TDO). Due to the increased TDO activity in the brains of individuals with genetic susceptibility to schizophrenia, the increase in these Kyn metabolites is exacerbated. The increase in KYNA levels in turn leads to excessive inhibition of glutamatergic and cholinergic neurotransmission, which can contribute to the onset of schizophrenia (Schwarcz and Hunter, 2007; Notarangelo et al., 2014).

The associations outlined above offer compelling avenues for further research into the role of T. gondii infection in the etiology and pathophysiology of schizophrenia. Understanding these complex interactions could potentially lead to the development of new therapeutic interventions targeting these specific mechanisms.

Depression is a common mental disorder characterized by significant and persistent low mood, slow thinking, cognitive impairment and reduced volitional activity (Xu et al., 2020). Depression is closely related to suicidal tendencies, and suicidal behavior is the most common complication of depression (Conejero et al., 2018). T. gondii infection has been reported to be associated with depression and suicidal tendencies (Okusaga et al., 2011), and chonic T. gondii infection may be a risk factor for depression and suicidal behavior (Kamal et al., 2022). After T. gondii infection, the host brain releases inflammatory cytokines, leading to neuroendocrine and immune system dysfunction and increasing the risk of depression in the host by exacerbating anxiety and depressive-like behavior (Bay-Richter et al., 2019).

Serotonin (also called 5-hydroxytryptamine, 5-HT) is a neurotransmitter with high concentration in the cerebral cortex and nerve synapses, and it is an important substance regulated to nerve activity. T. gondii infection leads to IFN-γ production and brain IDO activation, which degrades tryptophan and causes a decrease in 5-HT synthesis, ultimately inducing depression and suicidal behavior (Ihara et al., 2016; Mahmoud et al., 2016). T. gondii bradyzoites reactivation promotes the conversion of 5-HT to its main metabolite, 5-hydroxyindoleacetic acid (Mahmoud et al., 2016). Therefore, the enhancement of the tryptophan catabolic shunt and serotonin conversion may be associated with the development of depression-like behavior in T. gondii-reactivated mice, which may be triggered by immune imbalance (Mahmoud et al., 2016). In addition, the increase in Kyn production mediated by IDO through the kynurenine pathway may induce core symptoms of depression, such as anhedonia, or further transform into downstream neuroreactive metabolites such as KYNA and QUIN. Increases in these metabolites can be detected in the serum of patients with depression (Mahmoud et al., 2016).

After T. gondii infection, IFN-γ and other proinflammatory cytokines induce the activation of guanosine triphosphate cyclohydrolase-1 (GTP-CH1), which reduces the levels of phenylalanine (Phe, a precursor to norepinephrine) and tyrosine (Tyr, a precursor to dopamine), and may lead to a decrease in the levels of norepinephrine (NE) and DA in the synaptic cleft (Figure 2C), subsequently resulting in the onset of depression (Hsu et al., 2014; Kamal et al., 2022). The levels of inflammatory cytokines in the serum of patients with depression, including interleukins and TNF, are significantly elevated, and may indirectly reduce the levels of neurotransmitters in the brain (Catena-Dell'Osso et al., 2011). In addition, research has shown that after infection, the promoter of the arginine vasopressin (AVP) gene in the host is hypomethylated, leading to increased AVP expression, increased testosterone secretion (Figure 2C), and ultimately reduces fear of cat urine odor in infected rats, which may be linked to the exhibition of suicidal behaviors (Hari Dass and Vyas, 2014).