Toxoplasmosis and Psychiatric and Neurological Disorders: A Step

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Toxoplasmosis and Psychiatric and Neurological Disorders: A Step toward Understanding Parasite Pathogenesis Haitham G. Abo-Al-Ela*

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Animal Health Research Institute, Agriculture Research Center, Shibin Al-Kom, El-Minufiya 7001, Egypt ABSTRACT: Toxoplasmosis, a disease that disrupts fetal brain development and severely affects the host’s brain, has been linked to many behavioral and neurological disorders. There is growing interest in how a single-celled neurotropic parasite, Toxoplasma gondii, can control or change the behavior of the host as well as how it dominates the host’s neurons. Secrets beyond these could be answered by decoding the Toxoplasma gondii genome, unravelling the function of genomic sequences, and exploring epigenetics and mRNAs alterations, as well as the postulated mechanisms contributing to various neurological and psychiatric symptoms caused by this parasite. Substantial efforts have been made to elucidate the action of T. gondii on host immunity and the biology of its infection. However, the available studies on the molecular aspects of toxoplasmosis that affect central nervous system (CNS) circuits remain limited, and much research is still needed on this interesting topic. In my opinion, this parasite is a gift for studying the biology of the nervous system and related diseases. We should utilize the unique features of Toxoplasma, such as its abilities to modulate brain physiology, for neurological studies or as a possible tool or approach to cure neurological disease. KEYWORDS: Apicomplexa, behavioral disorder, mental health, personality changes, Toxoplasma gondii, toxoplasmosis, transcripts change

1. INTRODUCTION Several infectious agents, such as Toxoplasma gondii, cytomegalovirus, herpes simplex virus, and influenza virus, are in the pool of causative agents that are most commonly associated with various mental and behavioral disorders. In a chronic infection, the cyst form of T. gondii is generally located in various tissues; however, they prefer to stay in brain tissues rather than muscle tissues. Several studies have suggested that T. gondii is responsible for a series of neurological problems, which is becoming established as fact lately. Previously, Grimwood et al.1 detected a toxofactor, a teratogenic toxin produced by T. gondii tachyzoites, which might be responsible for congenital abnormalities particularly in the central nervous system (CNS) in exposed animals and may get transmitted to the fetus without direct transmission of the parasite. T. gondii can infect humans and all warm blooded animal species. The primary route of infection in humans is either through consumption of undercooked meat that harbors bradyzoite stage parasites or by drinking water or ingesting food contaminated with T. gondii oocysts (shed by infected felines, which are definitive hosts). In addition, a second possible route of infection is transplacentally (vertical) from infected mother to fetus, causing a congenital form of toxoplasmosis. Several host−parasite interaction studies on toxoplasmosis have indicated that gene expression changes in host cells leading to neurological disease conditions are supposed to be a result of T. gondii infection, 2−12 but the underlying © XXXX American Chemical Society

mechanisms remain unclear. Recently, T. gondii was used as a model to study gene−environment interaction relevant to psychiatric diseases.13 This review discusses the available molecular evidence suggestive of T. gondii infection mediated alterations to host cellular processes and resulting psychoneurological disorders.

2. A HINT REGARDING POTENTIAL NEUROLOGICAL, PSYCHIATRIC, AND BEHAVIORAL DISORDERS ASSOCIATED WITH TOXOPLASMOSIS On the level of behavioral changes, in a previous study on a large number of psychiatric inpatients, Hinze-Selch et al.14 reported that toxoplasmosis can modulate behavior and personality traits. T. gondii infection in mice caused anxietylike behavior, altered spatial memory, and altered recognition of social novelty.15 According to a questionnaire on 37 immunocompetent patients with acute toxoplasmosis, 52% of the patients suffered from difficulty concentrating, and 27 of 31 patients experienced a moderate to severe reduction in their overall mental and physical health after the first 2 months of illness. These reductions continued over the next 2 months in some cases.16 Strikingly, latent toxoplasmosis has been significantly linked to increased risk of traffic accidents, and accordingly, asymptomatic acquired infection represents a Received: April 23, 2019 Accepted: June 19, 2019 Published: June 19, 2019 A

DOI: 10.1021/acschemneuro.9b00245 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX

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ACS Chemical Neuroscience

modulate host cell gene expression and suppress host response to infection, as well as these contribute to other processes needed for parasite pathogenesis, which in turn might result in other associated behavioral or neurological changes. Interestingly, the first approach of T. gondii without invasion is sufficient to induce certain alterations in gene expression in the host,2 suggesting the presence of potential secreted proteins or molecules that act as messengers to possibly pave the road for invasion or rewire the host genome. During early infection, a considerable number of genes associated with immunity, including pro-inflammatory genes, are upregulated in host cells,2 and of course, they are induced to serve the host immune system. However, some or all of these genes might help T. gondii invade in one way or another. Later, these alterations will begin to modulate host cell transcripts related to various processes (i.e., glycolysis, cholesterol biosynthesis, carbohydrate and lipid metabolism, transcriptional regulation, protein synthesis, targeting, and degradation, cell signaling, inflammation, cell adhesion and cytoskeleton, nucleotide and amino acid metabolism, cell cycle, and apoptosis);2 therefore, all of these processes will be reflected in the host cell proteome, which is sufficient to reprogram cell metabolism.3 Of these, T. gondii specifically upregulates transcript levels involved in anaerobic glycolysis but not oxidative phosphorylation in host cells.2 In addition, Toxoplasma tachyzoites were found to specifically modulate host cell transcription of c-Myc in a rapid and sustained manner;28 also T. gondii was found to specifically change certain microRNAs (miRNAs),29 which will be discussed in section 3.2. Another way that T. gondii subverts the host cell is to inhibit host cell apoptotic pathways; the inhibition process is mostly centered around the manipulation of host transcription with a special focus on genes implicated in the prosurvival/antiapoptotic response.4 In addition to an upregulation in miRNA, such as miR-132 (will be discussed later), four genes (apoptotic peptidaseactivating factor 1 (APAF1), protein phosphatase 2 regulatory subunit B′ epsilon (PPP2R5E), mitogen-activated protein kinase 3 (MAPK3), and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS)) were downregulated following T. gondii infection where they play important roles in a wide range of cellular processes.5 Notably, the rhesus (Rh) blood group plays a role in modulating brain function in latent toxoplasmosis; toxoplasmosis-associated intelligence was higher in RhD-negative subjects than RhD-positive subjects and Toxoplasma-free peers,30 a case needs more interpretation. In another way, 14-3-3 is a protein kinase-dependent activator of tyrosine hydroxylase,31 which is involved in dopamine metabolism. Currently, the function of 14-3-3 protein is not well understood, but it may be involved in cell proliferation and survival and the inhibition of apoptosis in parasitized cells.32 Recently, Kaplan et al.33 reported that 14-33 protein has a role in axon growth and regeneration. Moreover, 14-3-3 protein levels are used as an indicator for some neurological problems.34 Importantly, mammals, including humans, have copies of the gene encoding this protein. However, impressively, Koyama et al.35 detected a 14-3-3 protein homologue during the enteroepithelial stages of parasites and sporozoites in felines, and this protein also contained two isoforms in the tachyzoite stage. One of these isoforms is mainly located in the cytosol with low membrane association, while the minor isoform was found only in detergent-resistant lipid rafts.36

serious, underestimated public health and economic problem.17 The association between T. gondii infection and suicidal behavior has been studied. In a recent study in Korea, high levels of T. gondii IgG antibodies (latent infection) were found in 13.5% of the examined subjects that attempted suicide. Compared with seronegative subjects, T. gondii IgG seropositive subjects that attempted suicide showed high depressive symptoms and state anxiety. Additionally, investigations revealed a significant difference in Hamilton Depression Scale (HAMD) scores in terms of depressed mood and guilty subscales, Columbia Suicide Severity Rating Scale (C-SSRS) scores with higher values in the severity and lethality subscales, and State-Trait Anxiety Inventory (STAI) scores in the STAI-State scale but without significant differences in the STAI-Trait scale. In contrast, the Korean Barratt Impulsiveness Scale (BIS) showed no significant difference between the seropositive and seronegative groups.18 With regard to psychiatric disorders, an induction of amyloid-beta (Aβ) immunoreactivity and hyperphosphorylated tau has been reported during toxoplasmosis, making T. gondii a high risk factor for Alzheimer’s disease.15,19 In addition, Brown et al.20 suggested that maternal exposure to toxoplasmosis (evidenced by elevated maternal IgG antibodies to Toxoplasma) is a potential risk factor for schizophrenia; however, it is currently excluded as a cause of schizophrenia. de Witte et al.21 concluded that increased exposure to neurotropic pathogens, including T. gondii, after birth is not associated with schizophrenia. In contrast, a meta-analysis on the association of T. gondii with schizophrenia, bipolar disorder, addiction, and obsessive compulsive disorder uncovered a significant link. Obviously, the strength of association increases with higher T. gondii IgG antibody titers. Acute toxoplasmosis does not seem to be involved in schizophrenia, but chronic infection does. Additionally, gender and IgM antibodies are not moderators of T. gondii infection and psychiatric disorders.22 The relationship between toxoplasmosis and schizophrenia has been thoroughly discussed by Fuglewicz et al.23 and Henriquez et al.24 However, the underlying physiological link between toxoplasmosis and schizophrenia remains unclear. For addressing and more thoroughly examining these issues, Toxoplasma significantly reduces gray matter density in particular parts of the brain in infected schizophrenic patients; however, no such evidence was noted in T. gondii-negative schizophrenic patients and between T. gondii-infected and noninfected healthy controls.25 In this sense, T. gondii does not seems to be the main effector for schizophrenia, but the parasite may potentially increase the risk of schizophrenia under specific conditions or in individuals with particular predispositions. This suggestion is supported by a previous analysis in which only 0.5−1% of Toxoplasma-infected persons developed schizophrenia during their lifetime.26,27 More recently, Kannan et al.13 found that genetic predisposition to psychiatric disorders, including schizophrenia, modulates the neurobehavioral consequences associated with chronic T. gondii infection.

3. MOLECULAR ASPECTS AND GENE EXPRESSION CHANGES DURING TOXOPLASMOSIS Recent evidence has shown that T. gondii remodels the host intracellular processes to obtain the required nutrients for its survival as well as to complete its life cycle. To accomplish these goals, T. gondii secretes effector proteins, which can B


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Table 1. Focused Attention on the Functions of Some Important Subunits of CORVET and HOPS Complexes in Toxoplasma gondii56−58 name of the protein BEACH domain-containing protein (BDCP) Vps8

Both BDCP and Vps8 Vps9 Vps11 Vps11, Mon1, Vps18, Vps39, and Vps9

function Required for morphologies of rhoptries and the vacuolar compartment. Assists in invasion and intracellular growth processes.

Critical for invasion, secretory organelle biogenesis, and gliding motility. Involved in T. gondii growth and egress in vitro. Important for the protein trafficking of dense granules, a subset of micronemes, rhoptries, and vacuolar compartment. Essential for the correct targeting of other Vps subunits associated with CORVET/HOPS complexes. Dictates the accurate targeting of the putative casein kinase 3 like and the TgASP3 maturase. Localized at restricted areas of the endomembrane system and associated with a Rab5 subcompartment that assembles with CORVET, as is known in many organisms. Vital for T. gondii virulence in vivo and its survival. Regulates endosome vesicle trafficking via the Rab5 guanine nucleotide exchange, affects secretory organelle biogenesis, regulates the ROP protein maturation, and plays a role in host cell invasion. Required for the de novo biogenesis of dense granules, micronemes, and rhoptries, thus affecting parasite invasion, motility, egress, intracellular growth, and survival. Facilitates association of the Vps8 and BDCP proteins to the endomembrane system of T. gondii, secured by Vps11. Essential for the targeted transport of the dense granule proteins and rhoptry proteins.

Gene expression of 14-3-3 isoforms showed differential levels ranging from downregulation to upregulation, and some isoforms are constitutively expressed upon Toxoplasma invasion in vitro.32 Tg14-3-3 induced a hypermotility and hypermigratory phenotype of infected dendritic cells and microglia,37 suggesting its role in dissemination of the parasite in the host tissue. In addition, Tg14-3-3 regulates host proteins that are involved in key cellular processes, including cell migration and translational initiation.38 To better understand the effect of T. gondii on the motility of monocytes, Cook et al.39 found that the parasite impairs a set of processes that modulate cellular adhesion and motility through disruption of focal adhesion formation and β1 integrin signaling. The aromatic amino acid hydroxylase, T. gondii tyrosine hydroxylase, depends on the cofactor biopterin for catalytic activity.31 The pterin-4a-carbinolamine dehydratase enzyme is encoded in the T. gondii genome and showed great similarity to the human enzyme. This important enzyme is involved in the recycling of biopterin, and its secretion may result in the supply of biopterin from the host.31,40 Intriguingly, guanosine-5′triphosphate cyclohydrolase, which is upregulated in T. gondiiinfected cells, plays a role in biopterin synthesis.2,41 The parasite uses these genes and their products in their metabolism and activities. Most studies carried out on the molecular aspects of Toxoplasma are focused on immunological biology or virulence of the parasite, trying to find a possible drug or way to overcome the parasite, which is important. However, we should exploit this parasite to study the nervous system in both normal and disease conditions. 3.1. Approach on Toxoplasma Genome Contributions in Parasite Pathogenesis. Every stage in the parasite’s life cycle has genes that serve the strategy of this stage. There are various changes in the microenvironment of the parasite ranging from downregulation to upregulation of gene expression among all stages in the life cycle (tachyzoites, merozoites, sporozoites, and oocysts).42,43 For example, surface antigen 1 (SAG1 or SRS29B) and many dense granule, rhoptry, and microneme (MIC) proteins are not expressed in merozoites (the first developmental stage in the feline host) and are mostly important in the invasive stage. However, many metabolic pathway-related genes are upregulated, reflecting the specific growth requirements during the merozoite stage.43 Importantly, humans44,45 and other vertebrates46 encode an

arrestin gene family (including surface antigen gene (SAG)) that specifically dampens cellular responses to stimuli such as neurotransmitters and hormones.46 SRS and SAG gene families encode structurally similar, but unrelated, surface antigens in Apicomplexa,47 suggesting that T. gondii may modulate these genes in the host. In additional support for strategic infection and virulence, T. gondii encodes the SRS gene superfamily that acts as a surface adhesion molecule, which mediates attachment to host cells, regulates parasite virulence in acute infection, and stimulates host immunity.48−50 After cyst rupture in chronic infection, surface SRS antigens on bradyzoites, mainly SRS9, facilitate the invasion of uninfected host cells, maintain parasite persistence, and play a role in the reactivation of chronic infection in the intestine.50 This family is differentially regulated depending on the strain and the parasite’s developmental stage; it may also be the key family that T. gondii uses to establish chronic infection in the intermediate host48−50 in which the SRS gene family, particularly SRS9, is mainly active during the bradyzoite stage (chronic infection) and regulates the switch from acute to chronic infection.49,50 In addition, T. gondii-derived heat shock protein 70 (TgHSP70)51 and glycosylphosphatidylinositols52 act as a ligand for Toll-like receptor (TLR) 2 or TLR4, as well as a profilin-like protein that acts as a ligand for TLR11,53 which proves the existence of the possible hijacking tools of the T. gondii genome. Dense granules, rhoptries, and micronemes are proteins of high interest in parasite pathogenesis and as potential targets for drugs (will be discussed later in this review). During the replication of the parasite, dynamin-related protein B (DrpB) is necessary for de novo biogenesis of secretory organelles. DrpB knockout is sufficient to produce a new generation of parasites deprived of micronemes and rhoptries. Additionally, DrpB is required for parasite intracellular development and for the processes of host cell egress, gliding motility, and invasion.54 More importantly, there are two essential membrane tethering complexes (class C core vacuole/endosome tethering [CORVET] and homotypic fusion and vacuole protein sorting [HOPS]) that are essential for early (CORVET) and late (HOPS) endosome transition, endolysosomal trafficking pathways, and lysosome biogenesis.55,56 Generally, CORVET and HOPS complexes contain four subunits, namely, vacuole C


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ACS Chemical Neuroscience protein sorting (Vps), but in T. gondii, they contain ten Vps. T. gondii contains important functional CORVET and HOPS complexes, and their proteins could be implicated in endolysosomal trafficking. A selective analysis of some of these associated proteins delineated several important functions, which are summarized in Table 1.56,57 3.1.1. Toxoplasma gondii Secretory Organelles. T. gondii depends on unique secretory organelles, especially rhoptries that facilitate its path to host cell invasion, internalization and survival within the host cell, therefore giving rise to complete control of the host cell. The contents of organelles, rhoptries, dense granules, and micronemes, have the ability to modulate the expression of many host genes. A subset of novel proteins, including dense granule proteins (GRA1, -2, -5, and -7 and T. gondii protease inhibitor-1), MIC proteins (MIC1, 2, 4, 5, 6, 8, 10, and 11; AMA1, M2AP, and SUB1), surface antigens (SRS1 and SAG1, 2, and 3), and other secretory proteins (Cyp18 and PDI) have been identified as secretory products, excretedsecreted antigens (ESAs), from T. gondii,59 and there is great progress in the research on this area. In this section, I will mention some examples of these secretory proteins because of their potential importance in modulating host cell molecular processes and because they may also act as a target for antitoxoplasmosis drugs. 3.1.1.1. Microneme. Microneme proteins are the main players in the parasite life cycle; they mobilize to the parasite surface to aid in gliding motility, migration, and host cell attachment. Carruthers and Tomley60 have reviewed these proteins, including the important MIC group. For example, TgSUB1, the first known subtilisin-like serine protease, is a mediator of microneme protein processing and may be involved in proteolysis during invasion.61 In contrast, TgSUB2, a subtilisin-like serine proteinase that localizes to rhoptries, cannot be disrupted, which is essential for parasite life and associates with rhoptry protein ROP1.62 3.1.1.2. Dense Granule. The function and mechanism of action of dense granules have been thoroughly reviewed by Nam63 and Mercier and Cesbron-Delauw.64 Approximately 22 GRA genes (GRA1, GRA2, GRA3, GRA4, GRA5, GRA6, GRA7, GRA8, GRA9, GRA10, GRA12, GRA14, GRA15, GRA16, GRA17, GRA19, GRA20, GRA21, GRA22, GRA23, GRA24, and GRA25) have been identified;12,64−69 some of these genes have been studied; however, others are under investigation. For example, GRA16 is transported through the parasitophorous vacuole membrane (PVM) and reaches the host cell nucleus by an unknown mechanism. In the host nucleus, GRA16 modulates host gene expression and binds two host enzymes, herpesvirus-associated ubiquitin-specific protease (HAUSP) and protein phosphatase 2A (PP2A), to form a complex that affects several functions, including cell-cycle progression, as well as positively regulates the intracellular levels of the tumor suppressor p53 in human cells. The GRA16 gene is greatly involved in the virulence of the parasite in the type II strain but not in the virulence of the type I strain,66 possibly because the type I strain depends on other virulence factors. In another example, GRA24 traffics to the host nucleus and directly interacts with p38α, resulting in activation of the host kinase that triggers the expression of pro-inflammatory cytokines and chemokines (e.g., interleukin (IL) 12p40 and MCP-1/CCL2) and upregulates the transcription factors Egr-1 and c-Fos, which in turn lead to long-term alterations in the host cell transcriptome related to these factors.69 In general,

GRAs have essential functions to the parasite, such as GRA1 and GRA10, which have a significant function in the growth and propagation of T. gondii.65,70 GRA10 induces adherence activity in macrophages, and as it is a calcium binding protein, it modulates intracellular calcium release.70 In addition, GRA6 has a regulatory role in the activation of the transcription factor nuclear factor of activated T cells 4 (NFAT4) via a calcium modulating ligand that in turn modulates the expression of chemokines such as Cxcl2 and Ccl2 in infected Toxoplasma cells. This pathway is essential for the full virulence of the parasite.71 Toxoplasma cathepsin Cs encode the papain family cathepsins cathepsin C 1, 2, and 3 and cathepsin B and L. These cathepsins have crucial roles in tachyzoite parasite growth and differentiation. Interestingly, following knockout of cathepsin C 1, cathepsin C 2 showed upregulation without affecting tachyzoite invasion and growth, suggesting cathepsin C 2 as a substitute for cathepsin C 1.72 3.1.1.3. Rhoptry. Rhoptries are apical organelles that contain a wide range of key molecules used by parasites to invade host cells and co-opt host functions; their biology has been discussed by Boothroyd and Dubremetz.73 During T. gondii invasion, rhoptry content is released into the parasitophorous vacuole (PV) and then into the host cell. In an interesting step to identify rhoptry protein content, Bradley et al.74 reported 38 novel proteins, including kinases, phosphatases, and proteases, and for the first time, they also identified rhoptry neck proteins, RONs. These proteins likely play a role in the parasite invasion process and were recently found to modulate the host transcriptome. Apparently, T. gondii targets the host nucleus by a variety of molecules that enable the parasite to coopt host cells, and it seems that rhoptries are highly implicated in this respect. Researchers identified a family of rhoptry proteins that are detected in all stages that were later named ROP proteins.75 Afterward, research was continued on this family. As a result, the following ROP proteins were identified: ROP1 (facilitates host cell penetration),76 ROP2 (a component of the PVM),77,78 proteinase cathepsin B (toxopain-1, localizes to the rhoptries and directly contributes to the invasion process),79 and Na+/H+ exchanger2 (NHE2) (has a possible role in osmotolerance).80 TgROP9 was expressed in all stages with the exception of the bradyzoite stage. TgROP9 has a distribution pattern that differs from other dense granule and microneme proteins.81 3.1.1.4. A Spotlight on the Interaction between Toxoplasma Secretory Proteins and Host Cells. Prior studies have addressed the mechanisms by which T. gondii overcomes the host immune response. Reportedly, upon invasion, a set of proteins are secreted by T. gondii to facilitate the process of the parasite invasion and pathogenesis. One of these proteins is ROP16, an important polymorphic rhoptry protein, which moves through the host cell to activate the signaling pathways of host signal transducer and activator of transcription (STAT) 3, 6, and 5, as well as to maintain this activation,8,9 which is dependent on signaling of the host cell adaptor molecules, particularly TLR and myeloid differentiation primary response 88 (MyD88). However, this activation is independent of any recognized T. gondii-triggered molecules linked to MyD88 (IL1β, IL18, TLR2, TLR4, TLR9, and TLR11) in infected cells. Moreover, ROP16 plays a role in curbing the production of interferon gamma (IFNγ)-induced nitric oxide by microglial cells, astrocytes, and lipopolysaccharide-induced cytokine D


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ACS Chemical Neuroscience synthesis in macrophages. Notably, the parasite mediates the synthesis of host cell arginase-1 via the ROP16 and STAT6 pathways, and subsequently, the available levels of the essential amino acid arginine are affected. This evidence further indicates that increasing the available host polyamines supports T. gondii replication; this goal could be achieved through induction of host arginase. In this way, ROP16 may act as a main regulator of parasite replication and as a possible mechanism to increase transmission potential.10,12 The different strains of T. gondii use diverse ways to activate host macrophages (Figure 1), which depend on the specific

There is a potential link between the genome structure (gene content or noncoding regions) of T. gondii and its modulatory action on the level of gene transcripts in infected human neuroepithelial cells; this link was observed through detecting changes in host cell transcripts that ranged from 78 to more than 1000 genes in infection with different strains of Toxoplasma. An overlap between 119 RefSeq genes was detected between type I and type III strains;7 the similarities between type I and type III strains have been shown in a previous study through many identical alleles at many loci.88 Activated STAT3 and STAT6 (by the rhoptry protein, ROP16) were more pronounced in type I or type III strains than in type II strains. Tyrosine-phosphorylated STAT3 is localized to the host cell nucleus during early infection, but later in the type II strain only, its level is sharply decreased in the nucleus, presumably because of the sequence difference (57 single-nucleotide polymorphisms, SNPs) that was detected between the type II allele and the type I and III alleles in ROP16, which may modulate tyrosine phosphorylation. Coinfection with type II or type III strains showed obvious phosphorylation of STAT3 and STAT6, providing evidence that this property cannot be reversed or suppressed in type I or III.8 Type II strain, but not type I or III strains can elicit very high secretion of IL12p40.8 Additionally, deletion of ROP16 strongly induces IL12p40 production; thus, in the normal state, it downregulates IL12p40 production.10 Interestingly, type I ROP16 and GRA15 significantly promote host survival and protect against Toxoplasma-induced small intestine inflammation (ileitis) resulting from type II infection, and they are considered negative regulators of virulence during oral Toxoplasma infection.9,12 There were differences in gene expression in human neuroepithelial cells in response to infection with the three types of T. gondii. Compared with the control, T. gondii type I caused a more than 1.2-fold change in expression in nearly 3.3% of transcripts (1423 out of 43004) on a microarray. Curiously, type II and type III infections modulated only 0.4% and 1.1% (162 and 478 out of 43004) of transcripts, respectively.7 Another study found that 1173 annotated genes were differentially regulated between type II and III infections.12 These results provide an overview of gene transcript changes during acute infection among different types of T. gondii. Similar investigations in chronic infection could be beneficial and could provide us with a wider vision. 3.2. MicroRNA (miRNAs) in Toxoplasmosis. In general, noncoding RNAs, including miRNAs, have a key regulatory role in the levels of transcription and translation. Although little is known about the modulatory action of noncoding RNAs in toxoplasmosis, there is progress in the research in this sector. Mostly, the alteration in hosts’ miRNAs following Toxoplasma infection is related to immunity and apoptosis processes.89 In acute infection, T. gondii modulates the expression of a considerable number of miRNAs related to cancer pathways.90,91 Most altered miRNAs and their potential functions have been mentioned by Cai and Shen;11 however, miRNA expression in toxoplasmosis needs further thorough investigations. Specifically, miR-132 regulates neuronal and immune functions and is involved in the differentiation of dopamine neurons; moreover, its disruption is associated with different neurological disorders.92,93 In all types of Toxoplasma strains, miR-132 is highly upregulated during acute infection.5,94

Figure 1. Pathways used by the three types of Toxoplasma gondii to activate the host macrophages. The type II parasite uses the classical pathway of activation (GRA15 activates nuclear factor κ light-chain enhancer of activated B cells (NF-κB); however, types I and III use an alternative means (ROP16 activates the signal transducer and activator of transcription 6 (STAT6)).

genome component of the parasite, essentially, ROP16 and dense granule protein GRA15.12 The classical pathway, as illustrated in Figure 1, is accompanied by the upregulation of many genes, including IL12, therefore inducing host IFNγ, which suppresses parasite growth.82 The novel type II protein GRA15 interacts with specific types of proteins in mice named Luzp1 and AW209491.83 Luzp plays an essential role in the development of the embryonic brain and is involved in the regulation of a subset of noncoding RNA genes in the host.83−85 However, more interpretation is needed, and Luzp may be implicated in the underlying mechanisms that result in neurological disorders. Furthermore, ROP16 regulates host cell transcription during cell invasion in which it localizes to the nucleus and interacts with nuclear proteins. In neuronal cells, ROP16, in a p53dependent manner, upregulates the expression of p21 and downregulates the expression of host cell division protein kinase 6 (CDK6) and cyclin D1, important proteins for progression of the cell cycle G1 phase and G1/S transition, that results in partial alterations in cell apoptosis (∼12.47%) and cell-cycle arrest at G1 phase (60.77%).86 3.1.1.5. Different Responses Resulting from Diverse Types of Toxoplasma gondii. There are three distinct types of T. gondii, I, II, and III. Although there is great genetic similarity (more than 98%) between the strains of T. gondii,87 each strain has its own strategy to manipulate host immunity. There were differences in TgAaaH2 expression in bradyzoite, which was greater in nonvirulent type III than in virulent type I.31 E


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Figure 2. Simple schematic of the synthesis and metabolism of dopamine highlighting tyrosine, dopamine, homovanillic acid, and norepinephrine.

regulators of mammalian reproductive and social behaviors; any mutations affecting their function will result in behavioral defects.99 These neuropeptides also have a powerful effect on social recognition in rats.100 Continuous transcription of extrahypothalamic AVP requires testosterone101 via hypomethylation of the AVP promoter.102 Most strikingly, T. gondii causes hypomethylation of the AVP promoter, resulting in greater expression of this peptide in the MePD of infected male rats. Infected animals exposed to a cat odor showed a pronounced activation of vasopressinergic neurons. In further support of these findings, the accompanying loss of fear can be relieved by the systemic hypermethylation of the MePD-AVP promoter.98 In contrast, related to infertility, T. gondii can modulate the testicular epigenome; hypomethylation of CpG sites was detected in cAMP response element modulator (Crem), cAMP response element binding protein (Creb), and family member of heat shock protein 70 (Hspa1) gene promoters; these genes are vital for and highly expressed during spermatogenesis, and the methylation of CpG islands located in their promoters regulates its activity.103 Moreover, cross-talk between epigenetics and miRNA was reported, and histone modifications were found to regulate miR-212/132 transcription.93

Additionally, miR-132 upregulation modulates a set of important pathways that have a critical role in vital brain functions, translational initiation and regulation, meiosis, mitosis, carcinogenesis, and cell growth, differentiation, survival, and proliferation.5 Interestingly, the opposite was observed with chronic infection in which miR-132 showed downregulation in different brain regions.94 Alternatively, chronic infection (bradyzoite) has a greater effect in modulating host miRNA than does acute infection (tachyzoites),95 possibly because the parasite needs these changes at this time of its life cycle to get complete control over the host cell; thus, miRNAs may have a crucial role in this respect. T. gondii is postulated to modulate host gene expression via targeting trans-regulation factors.90,91 Toxoplasma infection causes a change in key miRNAs, miR-17−92 and miR-106b− 25 in host cells, specifically, miR-17 family members;29 the parasite has the ability to inhibit apoptosis in the infected host cell through targeting the STAT3−miR-17−92−Bim pathway, which is associated with increased miRNA-17−92 and decreased Bim.96 Toxoplasma modulates the host transcriptome, and the host transcriptional regulator c-Myc was found to be actively regulated by the parasite on a posttranscriptional level. This regulation of c-Myc was found in all types of Toxoplasma, indicating the essential role of cMyc. The induction of c-Myc occurred independently of STAT3, NF-κB, and p38 MAP kinase. Induced c-Myc was postulated to regulate many genes, such as those involved in cell proliferation, metabolism, apoptosis, and immune function.28 3.3. Epigenetic Modification Caused by Toxoplasma gondii. Epigenetic modification is another powerful tool that could be used by T. gondii to influence the biology of the host nervous system and to reach the goals of the parasite or to facilitate its pathogenesis. Microbial and viral agents are responsible for various epigenetic reprogramming of host genes.97 The poster-dorsal medial amygdala (MePD) in rats contains a node of the extra-hypothalamic vasopressinergic system, which contains many arginine vasopressin (AVP) neurons.98 Vasopressin and oxytocin neuropeptides are the main

4. DOPAMINERGIC SYSTEM: A POTENTIAL KEY FOR BEHAVIORAL CHANGES There is a great deal of evidence suggesting that dopamine and its metabolism (Figure 2) are greatly implicated in neurological disorders associated with chronic toxoplasmosis. This interpretation is corroborated by the following discussed findings. Dopamine pathways have been proposed to mediate motivation and desire more than pleasure;104 they have been hypothesized to be causative agents of behavioral alterations105 and neurological disorders27 in latent toxoplasmosis that are possibly mediated by alterations in dopamine (increases) and tryptophan (decreases) levels. As a result, these changes are accompanied by decreases in the level of the neurotransmitter serotonin, and tryptophan has a role in the synthesis of serotonin in the brain. Evidently, a low level of serotonin can cause depression and increase the risk of suicide.27 F


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Table 2. Comparison between Neurotransmitter-Level Changes in Brains of Mice during Acute Toxoplasmosis among Three Different Studies, Stibbs,115 Xiao et al.,5 and Gatkowska et al.116 parameters tested strain tested sample tested time of sampling age and sex dopamine DOPAC 3-MT HVA serotonin 5-HIAA HVA/dopamine ratio HVA/3-MT ratio 5-HIAA/ serotonin ratio norepinephrine

Stibbs115

Xiao et al.5

Gatkowska et al.116

T. gondii C56 Toxoplasma strains RH-2F (type I), Prugniaud T. gondii ME49 strain (type II) strain (type III) (PRU, type II), and CTG (type III) whole brain striatum hypothalamus, amygdala, hippocampus, part of parietal cortex, brainstem, and the prefrontal medial cortex from the rostral brain part 12 days 5 days postinfection 3 weeks postinfection (late acute infection) postinfection 7 weeks, females 6−8 weeks, females 10−12 weeks, males and females constant ↑ by 38% ↑ in both males and females a ↑ by 24% a a ↑ by 36% a ↑ by 40% ↑ by 19% ↑ constant ↑ by 20% a constant ↑ by 25% a ↑ by 7.8% ↓ by 14% ↑ in males; ↓ in females a

↓ by 15%

a

constant

constant

↑ in both males and females

↓ by 28%

a

↓ in males; ↑ in females

a

Unavailable data.

schizophrenia 1 (DISC1). DISC1 critically controls DRD1 via transcription and epigenetic levels in the striatal neuron and thereby affects the dopamine-related psychiatric symptoms.114 Furthermore, the dominant-negative form of DISC1, a psychiatric genetic risk factor, mainly for schizophrenia, modulates the neurobehavioral effects of chronic toxoplasmosis.13 Different neurotransmitter level changes have been recorded among different brain parts in mice during acute toxoplasmosis (Table 2), which resulted in conflicts and questions. A reduction in the expression and protein levels of metabolizing enzyme monoamine oxidase A (MAOA) in particular and in D1-like dopamine receptors (DRD1, DRD5) was reported in the striatum of the mouse brain,5 while homovanillic acid (HVA) exhibited considerable increases,115,116 suggesting that MAOA downregulation is insufficient to curb the increases in HVA. To support this finding, MAOA inhibitors partially decrease HVA levels.117 Furthermore, in another way, we can conclude how dopamine is increasing in Toxoplasma infection in which the DRD1 has a role in the negative feedback of dopamine release.118 Overall, the disruption of dopamine pathways, reflected by changes such as norepinephrine decreases, HVA increases, normal catechol-O-methyltransferase (COMT) levels, and a 24% increase in 3,4-dihydroxyphenylacetic acid (DOPAC, an indicator of intraneuronal metabolism of dopamine) together with parallel increases in 3-methoxytyramine (3-MT) (by 36%) and dopamine (by 38%), suggests inefficient intraneuronal metabolism of dopamine and increased dopamine metabolism in general.6,116 Additionally, the opposite is observed in some cases.115,116 Curiously, among the data in Table 2, it has been speculated that a fluctuation in the levels of neurotransmitters occurs during acute infection. These differences might result from differences in the parasite strains, sample types, sampling time, gender, or brain microenvironment status at the time of the experiment. Further explanations that involve tyrosine hydroxylase are discussed below.

NR4A2 (Nurr1), a transcription factor, has a pivotal role in dopamine signaling and in dopaminergic neuronal differentiation, maintenance, and survival. In addition, Nurr1 has a neuroprotective role. Nurr1 has been connected to several neurological diseases, such as Alzheimer’s disease, multiple sclerosis, and stroke.106 Moreover, Nurr1 has been found to play a role in behavioral changes related to sex differences in toxoplasmosis.107 Nurr1 might be implicated in the changes in levels of dopamine and its metabolites in toxoplasmosis in general and the congenital form of the disease in particular. These features could make Nurr1 an important molecule that plays a role during toxoplasmosis and a potential target for therapies for toxoplasmosis-associated disorders. Low dopamine activity in the prefrontal cortex may be linked to the negative/deficit symptom complex of schizophrenia.108 Disturbances in dopamine signaling have been linked to schizophrenia,108 and this finding has been confirmed through the success of using antipsychotic drugs for targeting D2, D3, and D4 dopamine receptors (DRD).109 Furthermore, some medications used for schizophrenia succeeded in inhibiting T. gondii replication and invasion;110 these medications appear to alter the microenvironment that the parasite attempts to achieve to complete its pathogenesis pathway. Owing to the hypothesis that T. gondii increases the risk of schizophrenia, polymorphisms in AKT1, a gene that is involved in cell survival as well as the development of interactions with neuronal dopaminergic signaling, is implicated in schizophrenia. Interestingly, this gene is activated or shows increased expression during T. gondii infection.111,112 Additionally, vasoactive intestinal peptide receptor 2 (VIPR2), which may have a role in the pathophysiology of schizophrenia,113 was upregulated during toxoplasmosis.88 In an interesting step to understand the gene network and miRNAs in the host in response to pathogens affecting the nervous system, including T. gondii, Carter112 delineated some schizophrenia susceptibility genes that are directly implicated in the pathogenesis of neurotropic pathogens. One of those genes is disrupted-inG


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neurotransmitters together with other changes in immunity, hormones, and other unknown factors. 4.1. Are the Cortex and the Amygdala the Main Contributors to Dopaminergic System Disruption during Toxoplasmosis? Although T. gondii infects all areas of the brain, the cortex is the most affected and damaged part, and the highest levels of IFNγ were recorded in the cortex compared with the different parts of the brain.124 Toxoplasma infection causes significant changes in the transcript levels in the frontal cortex of mice.6 Metabolites of dopamine are recorded at higher levels in the cortex than in controls, but these levels remain unchanged in the amygdala, while dopamine levels themselves remain unchanged in the cortex but are lowered in the amygdala. The cortex and the amygdala play a role in fear memory expression. The high levels of dopamine metabolites were associated with impaired fear memory consolidation. These could suggest the role of the cortex and the amygdala in fear memory dysfunction during toxoplasmosis. Norepinephrine levels were lowered in the cortex and the amygdala, and serotonin showed low levels only in the amygdala.124

In early chronic infections, dopamine levels increase by 14% compared with those in controls. Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) remained at normal levels in infected mice,115 but experimentally, dopamine tends to return to the control values.116 Generally, the robust release of dopamine and the high level of tyrosine hydroxylase during latent infection were confirmed through the intense immunostaining of encysted parasites using dopamine and tyrosine hydroxylase antibodies, particularly in the striatum, amygdala, and hippocampus,119 parts that mainly contain dopaminergic neurons, suggesting high activity of tyrosine hydroxylase in the basal ganglia and possibly reduced activity in noradrenergic neurons in the brainstem. However, this scenario is proposed to occur in acute infection in which dopamine is increased and norepinephrine is decreased. Notably, the genome of T. gondii comprises two genes encoding tyrosine hydroxylase (TgAaaH1 and TgAaaH2) that produces 3,4-dihydroxy-L-phenylalanine (L-DOPA),31 and T. gondii may directly modulate the biosynthesis of neurotransmitter secretion, including dopamine or serotonin.24 The two encoded enzymes catabolize the conversion of phenylalanine to tyrosine and tyrosine to L-DOPA. The two Toxoplasma genes are highly similar in the catalytic domain to mammalian tyrosine and phenylalanine hydroxylases. TgAaaH1 is constitutively expressed in all parasite stages, while TgAaaH2 expression was markedly triggered during bradyzoite differentiation.31 Thus, it appears that each enzyme has different biological roles during the parasite life cycle. As TgAaaH1 and TgAaaH2 proteins have higher substrate selectivity for tyrosine, tyrosine will mostly be converted to 31 L-DOPA. The first idea that comes to mind is that L-DOPA will be converted to dopamine because dopamine levels are high in the latent infection;27,115 in contrast, dopamine levels remain unchanged in acute infection.115 This finding might be because TgAaaH2, induced in the cyst formation stage, is mainly implicated in this action, and TgAaaH1 has no or only a minor role as it is constitutively expressed.31 Another possible explanation that the parasite needs L-DOPA in cyst wall formation, as observed in other apicomplexan parasites.31,120 Additionally, because L-DOPA is the precursor to dopamine, its higher levels cause an elevation in dopamine. Dopamine was found to be a growth enhancer for tachyzoite as well as to increase the destruction of cells in vitro,121 However, the level of the host tyrosine hydroxylase remained unchanged,122,123 and overexpression of the hydroxylase AAH2 gene did not affect the host dopamine levels.123 It appears that increased dopamine mainly resulted from the parasite itself, since dopamine is essential for T. gondii growth, even if this happens for a certain period; afterward, the host dopamine may play a role in the modified behavior. Considering this scenario, the dopamine increases may be a key mediator in the behavioral changes caused by T. gondii. For further explanation, acute toxoplasmosis has little or no effect on the noradrenergic system activity in males or females; however, there was a marked increase in dopaminergic and serotonergic system activities in males. The elevation in dopamine may be a result of improper reuptake at the synaptic cleft, which directs the metabolism of dopamine toward the production of HVA. In contrast, in chronic toxoplasmosis, monoamine indexes returned to nearly normal levels, particularly in males.116 This finding indicates that each stage of infection has specific needs that serve the parasite cycle. Moreover, the behavioral changes result from changes in

5. TOXOPLASMOSIS AND SEX-RELATED DIFFERENCES It seems that gender may alter the gene expression in response to T. gondii. In an interesting study performed by Xiao et al.,6 there was a difference in gene expression among males and females not only in the total number of genes but also on the level of gene types in latent infection in the frontal cortices of mice. Interestingly, only five gene transcripts (Prg2, Slpi, Sema7a, Amotl2, and Vapb) overlapped between infected females and males, but there was no clear explanation until now. In both sexes, Toxoplasma infection markedly modulated the expression of genes related to the nervous system including genes associated with a wide range of nervous system development and neurological system processes. The detected differences between infected males and females may be a result of the direct or indirect effects of sex hormones (androgen and estrogens) or their effects on immunity,125,126 and this could explain why some specific genes that are associated with immunity were altered in Toxoplasma-infected females but not in males.6 In a similar vein, both acute and chronic toxoplasmosis cases reported a higher mean concentration of testosterone in men but a lower concentration in women.127,128 To explore this further, Lim et al.129 reported that T. gondii infection triggers the expression of genes including the luteinizing hormone receptor, which is involved in the synthesis pathways of testosterone, and thus results in a profuse production of testicular testosterone only in male rats. Curiously, luteinizing hormone (LH) levels in the urine are decreased during toxoplasmosis,103 although it is known that LH is a main regulator of testosterone production via its indirect effect on Leydig cells. It seems that the parasite may utilize another means to increase testosterone levels. T. gondii also suppressed overall spermatogenesis (including testicular function, sperm motility, and sperm concentration and led to increased sperm abnormalities). This might be a result of the low level of LH, and the increase in the release of corticotropin-releasing factor (CRF) from hypothalamic neurons under the action of peripherally circulating cytokines caused by toxoplasmosis, and so leads to the suppression of the release of gonadotropin-releasing hormone (GnRH).103,130 H


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transcription factor Nurr1 in females but not in males in the chronic infection.107 In addition, miR-132 may have a role in such cases, as miR-132 regulates the differentiation of dopamine neurons by targeting Nurr1.92 Taken together, these could explain the differences between male and female responses.

Furthermore, it is known that cholesterol is critical for the biosynthesis of testosterone as well as in the parasite’s replication. T. gondii induces some genes involved in cholesterol biosynthesis; however, steady cholesterol biosynthesis is observed. T. gondii obtains cholesterol via controlling the low-density lipoprotein (LDL) trafficking pathway, because it cannot synthesize sterols through the mevalonate pathway.2,131 In contrast, the detected upregulation of mevalonate metabolic enzyme transcripts following the parasitic invasion may be a result of the host cell trying to substitute the subverted LDL trafficking pathway.2 More interesting, Li et al.94 reported that T. gondii can modulate miR-132 and brain-derived neurotrophic factor (BDNF) expression in a sex-dependent manner during chronic infection, and females were found to exhibit more susceptibility than males. In addition, sex differences play a role in changing the neurobehavioral manifestations of chronic infection,13 giving us more examples for the sex effect. 5.1. Alterations in Behavior among Males and Females. There is clear evidence that Toxoplasma can cause specific behavioral changes in a sex-dependent manner in the infected host, and these changes can facilitate predation by the definitive host. This therefore completes the life cycle of this parasite,6 which supports the manipulation hypothesis. Chronic toxoplasmosis alters the expression of genes involved in the maturation of the forebrain, including in the diencephalon and adenohypophysis, which are linked to a decreased aversion to cat odor in male mice.6 In addition, it was found that epigenetic changes are implicated in this behavior disorder.98 As elucidated before, testosterone levels differed between males and females. Testosterone is known to reduce fear in males.132 In female rats, the different stages of the estrus cycle and the accompanying hormonal changes were sufficient to disrupt female behavior toward bobcat urine.133 T. gondii-infected mice manifested neuronal death, loss of olfactory sensory neurons, and a significant decrease in Nmethyl-D-aspartate receptor gene expression (NMDAR is a receptor that plays a role in synaptic plasticity and cognition). Although the loss of olfactory sensory neurons has been reported in male and female mice, only males showed a reduction in olfactory sensitivity.15 The last finding has been supported through the observed downregulation in a number of olfactory receptor genes, while an upregulation of the slit homologue 1 gene (it has a role in CNS development and organogenesis) in male mice is the reason why male mice show a pronounced attraction to cat odor, which is contrary to nature or instinct. Additionally, Toxoplasma-infected male mice suffered from deficient memory, besides a downregulation in DRD4 gene expression.6 At the same time, DRD4 variants are associated with attention-deficit hyperactivity disorder (ADHD).134 Furthermore, neurotransmitters were differentially changed among males and females and among acute and chronic infections.116 One of the possible hypotheses regarding the different responses among males and females is that the parasite may aim to provide itself with the opportunity for transmission from mothers to their progeny, which may result in a relatively longer lifespan of the parasite. It also achieves better spreading and shedding.27 To support this hypothesis, a significant aversion to bobcat urine was seen in the Nurr1+/− female mice in comparison to control females; however, no change was seen in the Nurr1+/− male mice as compared to control males. This could suggest the possible role of the dopaminergic

6. CRITICAL REMARKS AND FUTURE PROSPECTS Apparently, T. gondii acts on different molecular levels to modulate its host systems, mainly the nervous system. T. gondii alters multiple neurological processes involved in neurogenesis, maturation of the forebrain, and sensory and motor coordination.6,7 In addition, previous studies found an association of toxoplasmosis with many psychiatric and behavioral disorders; these associations with different disorders are presumably due to differences in brain and personal psychological health status, personality attributes, different parasitic strains, or immune status, which in turn can change the pathological effect of the parasite or its action. In other words, because humans, as an intermediate or “accidental” host, are not generally the main prey or target for felines (in particular cats) or due to human’s high evolutionary level (for example, brain’s advanced capabilities and intelligence), toxoplasmosis may manifest in various forms of neurological disease that can in one way or another resemble what occurs in animals. Further supporting the idea that humans are not the main target for T. gondii, at least in the recent era, the T. gondii genome encodes a unique profilin, a ligand for TLR11, which is found in mice but not in humans. However, other pathogens such as uropathogenic Escherichia coli could use this receptor.53 Possible explanation that ancient humans could have been preyed upon by the wild feline species. As time went by, the human TLR11 might have become unnecessary, and the TLR11 gene sequence may have changed as a result of evolution, being interrupted by several stop codons.53 However, future studies may reveal a specific type of TLR that Toxoplasma uses in human. Most researchers worldwide concluded that Toxoplasma is a risk factor, and I agree with them, but it is now time to investigate how we can utilize the features of this parasite to study or cure some neurological problems, such as schizophrenia. We may study how this parasite changes behavior or deviates normal physiology of the brain or neurons of patients, as well as examine the contents of T. gondii’s genome, which in turn may help us to understand several neurological disorders. This parasite should be considered an opportunity for studying the molecular biological circuits of the nervous system. During the early revision period for this review, an interesting preprint by Bracha et al.135 validated the possibility of using T. gondii as a vector for intracellular delivery of therapeutic protein to the CNS.

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AUTHOR INFORMATION

Corresponding Author

*E-mail addresses: [email protected]; haithamgamal2@ gmail.com. ORCID

Haitham G. Abo-Al-Ela: 0000-0003-4157-5372 Notes

The author declares no competing financial interest. I


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(4) Sinai, A. P., Payne, T. M., Carmen, J. C., Hardi, L., Watson, S. J., and Molestina, R. E. (2004) Mechanisms underlying the manipulation of host apoptotic pathways by Toxoplasma gondii. Int. J. Parasitol. 34 (3), 381−391. (5) Xiao, J., Li, Y., Prandovszky, E., Karuppagounder, S. S., Talbot, C. C., Dawson, V. L., Dawson, T. M., and Yolken, R. H. (2014) MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway. Neuroscience 268, 128− 138. (6) Xiao, J., Kannan, G., Jones-Brando, L., Brannock, C., Krasnova, I. N., Cadet, J. L., Pletnikov, M., and Yolken, R. H. (2012) Sex-specific changes in gene expression and behavior induced by chronic Toxoplasma infection in mice. Neuroscience 206, 39−48. (7) Xiao, J., Jones-Brando, L., Talbot, C. C., and Yolken, R. H. (2011) Differential effects of three canonical Toxoplasma strains on gene expression in human neuroepithelial cells. Infect. Immun. 79 (3), 1363−1373. (8) Saeij, J. P. J., Coller, S., Boyle, J. P., Jerome, M. E., White, M. W., and Boothroyd, J. C. (2007) Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445, 324− 327. (9) Jensen, K. D. C., Hu, K., Whitmarsh, R. J., Hassan, M. A., Julien, L., Lu, D., Chen, L., Hunter, C. A., and Saeij, J. P. J. (2013) Toxoplasma gondii rhoptry 16 kinase promotes host resistance to oral infection and intestinal inflammation only in the context of the dense granule protein GRA15. Infect. Immun. 81 (6), 2156−2167. (10) Butcher, B. A., Fox, B. A., Rommereim, L. M., Kim, S. G., Maurer, K. J., Yarovinsky, F., Herbert, D. B. R., Bzik, D. J., and Denkers, E. Y. (2011) Toxoplasma gondii rhoptry kinase Rop16 activates STAT3 and STAT6 resulting in cytokine inhibition and arginase-1-dependent growth control. PLoS Pathog. 7 (9), e1002236. (11) Cai, Y., and Shen, J. (2017) Modulation of host immune responses to Toxoplasma gondii by microRNAs. Parasite Immunol. 39 (2), e12417. (12) Jensen, K. D. C., Wang, Y., Wojno, E. D. T., Shastri, A. J., Hu, K., Cornel, L., Boedec, E., Ong, Y.-C., Chien, Y.-h., Hunter, C. A., Boothroyd, J. C., and Saeij, J. P. J. (2011) Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell Host Microbe 9 (6), 472−483. (13) Kannan, G., Prandovszky, E., Severance, E., Yolken, R. H., and Pletnikov, M. V. (2018) A new T. gondii mouse model of geneenvironment interaction relevant to psychiatric disease. Scientifica 2018, 7590958. (14) Hinze-Selch, D., Däubener, W., Erdag, S., and Wilms, S. (2010) The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients. Folia Parasitol. 57 (2), 129−135. (15) Torres, L., Robinson, S.-A., Kim, D.-G., Yan, A., Cleland, T. A., and Bynoe, M. S. (2018) Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer’s disease in wild-type, C57BL/6 mice. J. Neuroinflammation 15 (1), 57. (16) Wong, W. K., Upton, A., and Thomas, M. G. (2013) Neuropsychiatric symptoms are common in immunocompetent adult patients with Toxoplasma gondii acute lymphadenitis. Scand. J. Infect. Dis. 45 (5), 357−361. (17) Flegr, J., Havlícek, J., Kodym, P., Malý, M., and Smahel, Z. (2002) Increased risk of traffic accidents in subjects with latent toxoplasmosis: a retrospective case-control study. BMC Infect. Dis. 2 (1), 11. (18) Bak, J., Shim, S.-H., Kwon, Y.-J., Lee, H.-Y., Kim, J. S., Yoon, H., and Lee, Y. J. (2018) The association between suicide attempts and Toxoplasma gondii Infection. Clin. Psychopharmacol. Neurosci. 16 (1), 95−102. (19) Swarbrick, S., Wragg, N., Ghosh, S., and Stolzing, A. (2019) Systematic review of miRNA as biomarkers in Alzheimer’s disease. Mol. Neurobiol., DOI: 10.1007/s12035-019-1500-y. (20) Brown, A. S., Schaefer, C. A., Quesenberry, C. P., Jr., Liu, L., Babulas, V. P., and Susser, E. S. (2005) Maternal exposure to

ACKNOWLEDGMENTS I would like to express my great gratitude to my parents, who have offered incredible support throughout both my life and education. I thank Eman El-Emam (Espitalia - educational videos channel, YouTube), whose video about toxoplasmosis inspired me during preparation of this review. I apologize to colleagues whose important contributions could not be cited due to space limitations.

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ABBREVIATIONS 3-MT, 3-methoxytyramine; 5-HIAA, 5-hydroxyindoleacetic acid; ADHD, attention-deficit hyperactivity disorder; ALDH, aldehyde dehydrogenase; APAF1, apoptotic peptidase-activating factor 1; AVP, arginine vasopressin; Aβ, amyloid-beta; BDCP, BEACH domain-containing protein; BDNF, brainderived neurotrophic factor; BIS, Korean Barratt Impulsiveness Scale; CDK6, cell division protein kinase 6; CNS, central nervous system; COMT, catechol-O-methyltransferase; CORVET, class C core vacuole/endosome tethering; Creb, cAMP response element binding protein; Crem, cAMP response element modulator; CRF, corticotropin-releasing factor; CSSRS, Columbia suicide severity rating scale; DBH, dopamine beta hydroxylase; DISC1, disrupted-in-schizophrenia 1; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde; DRD, dopamine receptor D; DrpB, dynamin-related protein B; ESA, excreted-secreted antigens; GnRH, gonadotropin-releasing hormone; HAMD, Hamilton Depression Scale; HAUSP, herpesvirus-associated ubiquitinspecific protease; HOPS, homotypic fusion and vacuole protein sorting; HVA, homovanillic acid; IFNγ, interferon gamma; IL, interleukin; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue; LDL, low-density lipoprotein; LDOPA, 3,4-dihydroxy-L-phenylalanine; LH, luteinizing hormone; MAOA, monoamine oxidase A; MAPK3, mitogenactivated protein kinase 3; MePD, poster-dorsal medial amygdala; MIC, microneme proteins; miRNA, microRNA; MyD88, myeloid differentiation primary response 88; NFAT4, nuclear factor of activated T cells 4; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; NMDAR, Nmethyl-D-aspartate receptor; PP2A, protein phosphatase 2A; PPP2R5E, protein phosphatase 2 regulatory subunit B′ epsilon; PV, parasitophorous vacuole; PVM, parasitophorous vacuole membrane; Rh, Rhesus factor; SAG1, surface antigen 1; SNPs, single-nucleotide polymorphisms; SRS, SAG1-related sequence; STAI, State-Trait Anxiety Inventory; STAT, signal transducer and activator of transcription; TgHSP70, T. gondiiderived heat shock protein 70; TLR, Toll-like receptor; VIPR2, vasoactive intestinal peptide receptor 2; Vps, vacuole protein sorting

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REFERENCES

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