About this Journal Submit a Manuscript Table of Contents
Journal of Parasitology Research
Volume 2012 (2012), Article ID 589295, 10 pages
http://dx.doi.org/10.1155/2012/589295
Review Article

Toxoplasma on the Brain: Understanding Host-Pathogen Interactions in Chronic CNS Infection

1Department of Biology, University of Nebraska at Omaha, Omaha, NE 68182, USA
2Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA

Received 11 August 2011; Accepted 4 January 2012

Academic Editor: Sandra K. Halonen

Copyright © 2012 Sushrut Kamerkar and Paul H. Davis. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Toxoplasma gondii is a prevalent obligate intracellular parasite which chronically infects more than a third of the world’s population. Key to parasite prevalence is its ability to form chronic and nonimmunogenic bradyzoite cysts, which typically form in the brain and muscle cells of infected mammals, including humans. While acute clinical infection typically involves neurological and/or ocular damage, chronic infection has been more recently linked to behavioral changes. Establishment and maintenance of chronic infection involves a balance between the host immunity and parasite evasion of the immune response. Here, we outline the known cellular interplay between Toxoplasma gondii and cells of the central nervous system and review the reported effects of Toxoplasma gondii on behavior and neurological disease. Finally, we review new technologies which will allow us to more fully understand host-pathogen interactions.

1. Introduction

Toxoplasma gondii belongs to the phylum Apicomplexa, which consists of intracellular parasites having a characteristically polarized cell structure and a complex cytoskeletal and organellar arrangement at their apical end [1]. This obligate intracellular parasite can infect and replicate within virtually any nucleated mammalian or avian cell [2, 3]. It is believed that the major transmission method of T. gondii to humans is the consumption of raw or rare meat [46]. In addition, vertical transmission of T. gondii is also possible, occurring when a female receives a primary infection while pregnant which can lead to fetal morbidity such as hydrocephaly. Indeed, T. gondii infection is a primary cause of fetal malformations in the United States [7]. Up to 80% of a population may be infected, depending on eating habits and exposure to felines, which serve as the definitive hosts and shed environmentally robust oocysts in feces [7, 8]. Oocysts can be stable in the environment for up to a year, may contaminate food or water supplies, and infect other warm blooded vertebrates [9]. A recent study suggested that oocyst-acquired infections are the most clinically severe form of infection, which may occur not just through direct cat fecal exposure, but contamination of municipal drinking water [10].

Two critical intracellular stages in the pathogenesis and transmission of Toxoplasma gondii are the rapidly replicating tachyzoite stage and the slower growing, cyst-forming bradyzoite stage. Initially, latent infections in humans were assumed to be largely asymptomatic. However, during the initial AIDS crisis, Toxoplasma became known as a major opportunistic pathogen [11]. As the host adaptive immune response weakens, parasite tissue cysts rupture and release bradyzoites through an unknown mechanism. These recrudescent infections permit parasite conversion to the rapidly-dividing tachyzoite stage and produce significant morbidity, including Toxoplasma encephalitis [12, 13].

Until recently, T. gondii chronic infections were considered largely innocuous in the otherwise healthy patient, despite observed neurological changes. However, more recent studies on model animals have suggested that behavioral changes are manifest following infection [14]. Moreover, recent associations have been made between parasite infection and neurological disorders, such as schizophrenia [15]. Hence, it is critical that the relationship between both host and parasite, and between infection and disease, be subjected to more analysis. Central to these issues is the involvement of the host immune response, which is only beginning to be delineated and understood.

2. Acute Infection and Dissemination

The most frequent cause of primary infection is the ingestion of Toxoplasma gondii tissue cysts. Surviving the gastric processes, the parasite excysts to cross into intestinal epithelium and continues propagation [16]. Due to advantageous intracellular localization, the parasite is largely protected from soluble, humoral, or cellular antimicrobial factors, although the degree of success may be dependent on the parasite genotype [17]. However, a T H 1 immune response is nevertheless triggered during this acute stage, as recently reviewed in [18, 19]. The parasite has developed adaptations which allow it to manipulate the innate immune system, frequently leading to continued proliferation in the gut tissue, despite the influx of lymphocytes and cells of the innate immune system [20]. Paradoxically, it is believed that these cells, particularly dendritic cells and macrophages, are intracellularly infected and grant the parasite the ability to spread hematogenously via a “Trojan horse” approach [2123].

Once in circulation, parasites are able to migrate within infected cells and remain in the tachyzoite state prior to activation of the adaptive immune response [24]. Thereafter, parasites somehow become confined to muscle and brain tissue [25]. In a process poorly understood, the parasites are believed to traverse the endothelial cells comprising the blood brain barrier. A recent study by Lachenmaier et. al suggests that infected murine brain endothelial cells promote infected leukocyte migration through the blood brain barrier [26]. Whether other mechanisms, such as extracellular parasite barrier penetration, are used to gain access to the CNS is still unknown.

3. Bradyzoite Formation

The chronic, robust bradyzoite stage is critical for the transmission of the parasite via carnivorism and likely accounts for parasite ubiquity. Tissue cysts are composed of host cells which may contain 100 or more individual parasites surrounded by a cyst wall produced during differentiation. The transition to the chronic stage is thought to be induced by exogenous stressors to the parasite, host, or both or may occur spontaneously depending on infected cell type [2730]. According to Blader and Saeij, neurons and muscle cells are terminally differentiated and withdrawn from the cell cycle. They have suggested a model in which tachyzoite growth is favored inside of growing cells, but when tachyzoites cannot manipulate the host’s cell cycle, bradyzoite development initiates [31].

The most physiologically effective method of bradyzoite stage induction in vitro is increasing the pH of the culture media to 8.0–8.2, although variations of this method exist [32, 33]. Exposure of Toxoplasma gondii to an alkaline media prior to host cell invasion enhances bradyzoite differentiation [34]. Alternatively, heat shock (43°C) of the host cells for 2 hours prior to invasion followed by parasite invasion for 2 hours at 37°C and additional heat shock of infected cells for 12–48 hours after infection is an induction method less harsh to host cells [32]. Chemical induction methods, such as the use of sodium arsenite, sodium nitroprusside, or a trisubstituted pyrrole (Compound 1), are also effective [32, 35, 36]. Nutrient deprivation, such as the amino acid arginine, slows growth and enhances differentiation [27, 37]. Simultaneous inhibition of pyrimidine de novo biosynthesis and salvage pathways (via low CO2) also induces slow growth and differentiation to bradyzoites [38]. Alteration of host cell gene expression has been shown to slow tachyzoites replication, which may induce bradyzoite specific gene expression [39]. Thus, application of exogenous stress to the parasite appears to consistently trigger the formation of the bradyzoite state in vitro.

Due to the clinical importance of the bradyzoite stage, and the ability to generate this stage in vitro, it has been the focus of several studies [12, 27, 33, 4042]. The T. gondii cyst wall membrane, largely consisting of glycoproteins, is thought to be critical in maintaining the structural and nutrient needs of the parasite while mitigating host immune system detection [4345]. Additional observable changes occur in subcellular organelles, including a decrease in dense granules, and an increase in micronemes and large amylopectin granules. The parasite downregulates cell division and enters a quiescent G0 state [28], and general protein translation slows considerably due to parasite eIF2 phosphorylation [46, 47]. Interestingly, knocking out an abundant protease inhibitor in the parasite led to enhanced bradyzoite formation in vitro [48]. Transcriptional profiles of high-resolution timecourse experiments of tachyzoites undergoing differentiation are available at eupathdb.org [4951]. These studies include parasite transcript measurements from multiple strains subjected to a variety of induction conditions, including CO2 starvation, sodium nitroprusside, alkaline media, or Compound 1 treatment. Results from these studies not only confirm the upregulation of known bradyzoite markers, but also reveal a novel set of early upregulated transcripts (Davis PH, manuscript in preparation).

According to Sullivan et al., the bradyzoite cyst form strongly contributes to the success of Toxoplasma in the following manner [12]: (1) the cyst survives gastrointestinal processes, allowing invasion of the small intestine; (2) the cyst is resistant to host immune response (and current drug treatments); (3) the parasites persist without perturbing host cells throughout the lifespan of the host; (4) bradyzoites in tissue cysts are infectious, lending to carnivorous transmission.

4. Immune Response to CNS Infection

Upon entering tissues of the central nervous system, the parasite establishes a delicate balance of low metabolic and proliferative activity, while avoiding robust host immune system activation [52]. Meanwhile, it is advantageous for the host to balance prolific replication of the pathogen with the potential for intense immunopathology. While most subclinical infections of Toxoplasma demonstrate this balance, it should be noted that the interplay between various host and parasite genotypes allows for considerable variation in observed immune response and course of infection [5357]. Due to the difficulties in studying human CNS infections, most reported information concerning the immune response in T. gondii CNS infection originates from murine models. In recognition of known immunological differences between mice and humans, cross-species comparisons of effector molecules can be difficult [58, 59]. However, these models have yielded substantial understanding of the cellular immunoregulation of Toxoplasma infection [19]. Several studies of the effects of Toxoplasma infection on cells of the CNS have been compiled in Table 1.

tab1
Table 1: The response of CNS-resident cells to Toxoplasma gondii infection.

Upon entry to the CNS, tachyzoite parasites appear to infect astrocytes, neurons, and microglial cells, possibly with different affinities. Parasite infiltration is followed by CD4+ and CD8+ T cell influx in a process still not fully understood, but which is critical for control of T. gondii CNS infection, and which can be activated via CD28 or ICOS stimulatory pathways [6064]. Infection and subsequent lymphocyte infiltration is reported to cause structural modifications to CNS tissues, based on two-photon image observations [65]. Cellular components of the innate response, such as macrophages and NK cells, are also able to enter the CNS during infection, but their role is less clear. A main feature of influxed activated T cells is the production of IFN-gamma, shown to be essential for the prevention of parasite reactivation in an immune cell-mediated manner [66, 67]. To a lesser degree, microglial and other cells also generate IFN-gamma, as well as several other pro- and anti-inflammatory cytokines and chemokines following infection [6872]. In vitro work suggests that astrocytes and microglial cells are able inhibit parasite replication upon activation [7375], possibly explaining why neurons are the dominant chronically infected cell type [76, 77]. Moreover, the process of parasite clearance appears reliant on host cell autophagy [78, 79]. However, a recent report suggests that microglial cells may function as a “Trojan horse” in the dissemination of recrudescent parasite infection [80].

During and following acute CNS infection by T. gondii, the host must maintain a balance of controlling parasite proliferation, while avoiding immunity-induced damage. The inhibitory effect of IL-10 is required to prevent immunopathology during primary infection, but not required to prevent immune hyperactivity during secondary challenge to T. gondii, nor required to generate a memory response [81]. IL-27 has also been described as immunosuppressive in the context of toxoplasmosis and may induce IL-10 production [8284]. Immune-related pathology is also believed to be locally controlled by inducible TIMP-1, an inhibitor of matrix metalloproteinases (MMPs) produced by astrocytes and other microglial cells [85]. Upon CNS infection by the parasite, T cells migrating into the CNS have shown increased expression of MMP-8 and MMP-10, proteins involved in tissue remodeling, cell migration, and inflammation. The absence of the MMP inhibitor TIMP-1 reduced parasite load approximately four-fold, but it is predicted that additional CNS damage would occur in the presence of untempered MMP activity [86, 87].

Once a chronic infection is established, the parasite is predominantly found in the bradyzoite stage within the CNS. Based on microscopic studies, cysts were located throughout the brain, but concentrated in the cerebral cortex, hippocampus, basal ganglia, and amygdala [88]. The cyst stage dominance may be due to at least two phenomena: first, the acute immune response may successfully clear cells infected with the tachyzoite stage, leaving only bradyzoite-containing cells to remain viable. Second, the interferon-gamma upregulation associated with the acute response may maintain parasite differentiation [27]. Recent studies have shown that, unlike extracellular parasites, cyst-bearing cells are not visible to CD8+ T cells, suggesting that such intracellular cyst structures are an effective means of immune evasion [89]. Alternatively, this data may be explained by the relatively low MHC class I displayed by neurons. Additionally, T cell behavior has been shown to be dependent on antigen availability in the CNS [65].

Of note, various alterations in the host immune response have been shown to allow recrudescent disease, hallmarked by parasite conversion back to tachyzoites and ultimately toxoplasmic encephalitis [90]. The clinical relevancy of this finding became apparent during the onsets of the AIDS epidemic [91]. However, in most immunocompetent conditions, parasite infections will remain in a chronic subclinical state (aside from possible behavioral modifications, discussed below) for the lifespan of the host. Whether bradyzoite cysts regularly (or randomly) burst open in immunocompetent hosts and quickly reinvade nearby cells is an unsettled question [13]. It is possible that infrequent cyst release is met with a robust memory response which eliminates some or all extracellular parasites prior to reinvasion. Or the bradyzoite cysts may simply be capable of outlasting the host. Likely, some combination of these events contributes to the long-lasting balance demonstrated by the interaction of the host and parasite, thus making it one of the most prevalent parasitic infections globally.

5. Exploring the Effects of Toxoplasma gondii on Behavior

Certain parasites have been known to selectively alter host behavior to enhance their transmission. Although latent infection with Toxoplasma gondii is among the most prevalent human infections, it has been assumed to be mostly asymptomatic, despite early work showing deleterious memory effects on murine models [92]. More recently, it has been found that the parasite has the ability to modify host behavior. Infected rats were shown to be less fearful of cats (the definitive host of the parasite) as compared to noninfected controls, thus conferring a sexual advantage to the parasite [93]. This has lead researchers to speculate whether the parasite may have similar effects on humans [14, 94]. It is unknown whether these behavioral changes in the host are due to the parasite alone, or are they due to the outcome of the host’s immune response against the parasite. Alternatively, such effects could be side effects of host illness or even a fortuitous byproduct, such as inducing the host to undertake greater risks to meet higher energy demands [95, 96]. For example, infected rats are more active than uninfected counterparts [97]. Intriguingly, infected rats are less neophobic (fear of novelty) to each novel stimuli presented, as compared to uninfected rats [98]. While some infected rats showed a strong aversion to areas with cat odor, a proportion of infected rats showed a potentially sexual attraction to cat-treated areas [93, 99].

The behavioral manipulation hypothesis postulates that a parasite will specifically manipulate host behaviors essential for enhancing its own success [14, 100]. However, the neural circuits involved in learned fear, anxiety, and innate fear overlap to a great extent, suggesting that the parasite may disrupt all of these nonspecifically [95]. One group has reported that the density of cysts in the medial and basolateral amygdala is almost double that in other structures such as hippocampus, olfactory bulbs, and prefrontal cortex [95]. The amygdala performs a primary role in the processing of memory and emotional reactions, such as fear. This may be the reason why infected mice show a nonwildtype attraction to feline odor and/or have modified fear, or sexual arousal responses. Hence, in this context, the behavioral manipulation hypothesis would support the capacity of the parasite to ameliorate innate feline fear, and possibly replace it by a novel or feline attraction, while appearing to leave other domains unchanged [101]. To date, however, there is no known mechanism coordinating infected regions with changes in behavior.

To the degree that these can be measured, nonmemory-related cognitive functions, anxiety, and social behavior in infected mice are unchanged when compared to controls; yet, they experience profound and widespread brain pathology, motor coordination, and sensory deficits [102]. These changes could be due, in part, to hyperactive MMP proteolysis [103], and/or the creation of novel brain structures [65], as discussed above. It has been proposed that CNS modification following T. gondii infection may behaviorally affect human hosts, as well [96]. There have been published correlations between latent Toxoplasma infections and human behavioral changes such as: slower reactions, lower rule consciousness, decreased novelty seeking behavior and greater jealousy in men, and promiscuity and greater conscientiousness in women, as reviewed in [96]. Toxoplasma gondii can increase the dopamine levels in rodents [104]; this may be due to the inflammatory release of dopamine by increasing cytokines such as interleukin-2, or potentially by direct parasite production. Many of the neurobehavioral symptoms that are postulated to be due to toxoplasmosis correlate to the general function of dopamine in the human brain.

6. Toxoplasma-Associated Psychiatric Sequelae

The dopamine imbalance between the mesolimbic and the mesocortical regions in the brain is suspected to play a role in the development of schizophrenia. This may permit a relationship between schizophrenia and toxoplasmosis [96]. Schizophrenia is one of the most prevalent and severe psychiatric syndromes. With onset often in young adulthood, schizophrenia is characterized by impairment in thought processing, perception, cognition, mood, and psychomotor behavior [15]. There is a growing interest in the role of parasites in the causation of psychiatric disorders, in addition to personality changes, and risk-taking behavior. Of note, drugs that have antipsychotic and mood stabilizing properties (which are used in the treatment of schizophrenia and other psychiatric disorders) may be augmented through their inhibitory impact upon T. gondii in infected individuals [94]. An example of this is the antipsychotic haloperidol and the mood stabilizer valproic acid, which most effectively inhibit Toxoplasma growth in vitro, although not in vivo [105].

To date, no causal link has been demonstrated, but correlative data is abundant. For example, 185 noninebriated automobile drivers in Turkey involved in a vehicular accident within a 6-month window were evaluated for toxoplasmosis. The cohort of drivers involved in accidents was substantially more likely to have T. gondii infection compared to the control (nonaccident) group: 33% versus 8.6% seropositive, respectively [106]. A number of studies have assessed seropositivity to Toxoplasma gondii in individuals with schizophrenia and other forms of severe psychiatric disorders, with inconsistent correlative results [107109]. In addition, Toxoplasma gondii encephalitis may manifest with symptoms similar to those of schizophrenia and other psychiatric disorders [110]. There have been a high number of cases with symptoms that included delusions, thought disorder, and auditory hallucinations in patients with AIDS and toxoplasmic encephalitis [15, 110].

Toxoplasma gondii infection has also been associated with obsessive-compulsive disorder in humans [15]. Men had “lower superego strengths (rule consciousness) and higher vigilance” as well as being “more expedient, suspicious and jealous.” These factors are associated with substance abuse, anxiety, and personality disorders. Women showed almost the opposite behavior: with higher superego strength and factors that suggested warmth, conscientiousness, and moral adherence. But both men and women were found to have more apprehension compared with uninfected controls [15, 96]. According to Flegr, differences in the level of testosterone may be another reason for these observed differences [96]. High testosterone individuals may be more susceptible to Toxoplasma infection via a less robust immune response, or observed behavioral changes could be the result of the parasite inducing testosterone availability in order to further impair the cellular immunity of the host. In a small study, seropositive men were found to have higher concentrations of testosterone than uninfected men; however, it is unknown whether high testosterone predisposes individuals to infection behaviorally or biologically, or whether the parasite indirectly drives testosterone levels. In an ongoing high-throughput cell-based screening study, overexpression of 17α-hydroxylase in human cells substantially increased the in vitro rate of Toxoplasma growth, while the inhibition of this transcript via siRNA decreased intracellular growth (Davis PH, manuscript in preparation). 17α-hydroxylase is a key metabolic enzyme responsible for converting cholesterol-like molecules into androgen precursors, such as testosterone. This finding suggests that testosterone-like sterols may directly benefit the growth of the parasite.

7. Future Directions

Due to the growing possibility that T. gondii infection can alter host behavior, there may be a renewed push for antiparasitic agents, as chronic Toxoplasma gondii is untreatable. Agent development may be difficult, however, due to the need for drugs to penetrate the blood-brain barrier, as well as the parasite cyst wall [111]. Moreover, even if the parasites could be removed from the neurons without creating additional tissue destruction, preexisting tissue pathology may preclude resolution of possible behavior-related sequelae. Recently, a study identified several compounds capable of inhibiting T. gondii tachyzoites in vitro, in addition to P. falciparum [112], and some of these compounds are being investigated for their antibradyzoite properties (Davis PH, manuscript in preparation).

In addition, the growing understanding of the complex immunoregulatory processes surrounding parasite infection may aid possible vaccine development [113]. However, Table 1 indicates the paucity of information on the interplay between the immune system and the bradyzoite stage, which may be a valuable avenue for future exploration. Future work may also be directed at delineating the process of parasite penetration through the blood brain barrier, as well as a deeper understanding of the molecular events in T cell control of infection. Much like the contributions of electron microscopy illuminated our understanding of apicomplexan organisms [114], so too does advanced imaging, such as bioluminescence and two-photon imaging, promise to provide greater details and real-time information on the workings of this parasite and its interactions with the host [65, 89, 115119]. Moreover, the precise role of antigens and host immune cells promises to be robustly detailed with tetramer-based molecular tools [61]. Finally, host modification, such that siRNA and overexpression of host genes, may illuminate critical cellular factors required for the parasite’s lifecycle [120]. Hi-throughput cell-based screening promises to hasten this understanding considerably.

Acknowledgments

The authors thank those whose work was cited and apologize for accidentally omitted studies. Financial support is from NIH NCRR P20 RR16469, NIAID 5F32 AI077268, NIGMS 8P20 GM103427, and the University of Nebraska at Omaha.

References

  1. J. P. Dubey, D. S. Lindsay, and C. A. Speer, “Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts,” Clinical Microbiology Reviews, vol. 11, no. 2, pp. 267–299, 1998. View at Scopus
  2. J. P. Dubey, “Advances in the life cycle of Toxoplasma gondii,” International Journal for Parasitology, vol. 28, no. 7, pp. 1019–1024, 1998. View at Publisher · View at Google Scholar · View at Scopus
  3. M. W. Black and J. C. Boothroyd, “Lytic cycle of Toxoplasma gondii,” Microbiology and Molecular Biology Reviews, vol. 64, no. 3, pp. 607–623, 2000. View at Scopus
  4. M. B. Lee, “Everyday and exotic foodborne parasites,” Canadian Journal of Infectious Diseases, vol. 11, no. 3, pp. 155–158, 2000.
  5. T. R. Slifko, H. V. Smith, and J. B. Rose, “Emerging parasite zoonoses associated with water and food,” International Journal for Parasitology, vol. 30, no. 12-13, pp. 1379–1393, 2000. View at Publisher · View at Google Scholar · View at Scopus
  6. J. P. Dubey and J. L. Jones, “Toxoplasma gondii infection in humans and animals in the United States,” International Journal for Parasitology, vol. 38, no. 11, pp. 1257–1278, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. A. M. Tenter, A. R. Heckeroth, and L. M. Weiss, “Toxoplasma gondii: from animals to humans,” International Journal for Parasitology, vol. 30, no. 12-13, pp. 1217–1258, 2000. View at Publisher · View at Google Scholar · View at Scopus
  8. J. P. Dubey, “Toxoplasmosis—a waterborne zoonosis,” Veterinary Parasitology, vol. 126, no. 1-2, pp. 57–72, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. J. P. Dubey, “Toxoplasma gondii oocyst survival under defined temperatures,” Journal of Parasitology, vol. 84, no. 4, pp. 862–865, 1998. View at Publisher · View at Google Scholar · View at Scopus
  10. J. L. Jones and J. P. Dubey, “Waterborne toxoplasmosis—recent developments,” Experimental Parasitology, vol. 124, no. 1, pp. 10–25, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Y. Wong and J. S. Remington, “Biology of Toxoplasma gondii,” AIDS, vol. 7, no. 3, pp. 299–316, 1993. View at Scopus
  12. W. J. Sullivan Jr., A. T. Smith, and B. R. Joyce, “Understanding mechanisms and the role of differentiation in pathogenesis of Toxoplasma gondii—a review,” Memorias do Instituto Oswaldo Cruz, vol. 104, no. 2, pp. 155–161, 2009. View at Scopus
  13. D. J. P. Ferguson, W. M. Hutchison, and E. Pettersen, “Tissue cyst rupture in mice chronically infected with Toxoplasma gondii. An immunocytochemical and ultrastructural study,” Parasitology Research, vol. 75, no. 8, pp. 599–603, 1989. View at Scopus
  14. J. P. Webster, “The effect of Toxoplasma gondii on animal behavior: playing cat and mouse,” Schizophrenia Bulletin, vol. 33, no. 3, pp. 752–756, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. A. Fekadu, T. Shibre, and A. J. Cleare, “Toxoplasmosis as a cause for behaviour disorders—overview of evidence and mechanisms,” Folia Parasitologica, vol. 57, no. 2, pp. 105–113, 2010. View at Scopus
  16. A. Barragan and L. David Sibley, “Transepithelial migration of Toxoplasma gondii is linked to parasite motility and virulence,” Journal of Experimental Medicine, vol. 195, no. 12, pp. 1625–1633, 2002. View at Publisher · View at Google Scholar · View at Scopus
  17. D. M. Foureau, D. W. Mielcarz, L. C. Menard et al., “TLR9-dependent induction of intestinal α-defensins by Toxoplasma gondii,” Journal of Immunology, vol. 184, no. 12, pp. 7022–7029, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Munoz, O. Liesenfeld, and M. M. Heimesaat, “Immunology of Toxoplasma gondii,” Immunological Reviews, vol. 240, no. 1, pp. 269–285, 2011. View at Publisher · View at Google Scholar
  19. E. D. Tait and C. A. Hunter, “Advances in understanding immunity to Toxoplasma gondii,” Memorias do Instituto Oswaldo Cruz, vol. 104, no. 2, pp. 201–210, 2009. View at Scopus
  20. A. M. Pollard, L. J. Knoll, and D. G. Mordue, “The role of specific Toxoplasma gondii molecules in manipulation of innate immunity,” Trends in Parasitology, vol. 25, no. 11, pp. 491–494, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. L. M. Da Gama, F. L. Ribeiro-Gomes, U. Guimarães Jr., and A. C.V. Arnholdt, “Reduction in adhesiveness to extracellular matrix components, modulation of adhesion molecules and in vivo migration of murine macrophages infected with Toxoplasma gondii,” Microbes and Infection, vol. 6, no. 14, pp. 1287–1296, 2004. View at Publisher · View at Google Scholar
  22. N. Courret, S. Darche, P. Sonigo, G. Milon, D. Buzoni-Gâtel, and I. Tardieux, “CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain,” Blood, vol. 107, no. 1, pp. 309–316, 2006. View at Publisher · View at Google Scholar · View at Scopus
  23. A. Barragan and N. Hitziger, “Transepithelial migration by Toxoplasma,” Sub-Cellular Biochemistry, vol. 47, pp. 198–207, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. H. Lambert and A. Barragan, “Modelling parasite dissemination: host cell subversion and immune evasion by Toxoplasma gondii,” Cellular Microbiology, vol. 12, no. 3, pp. 292–300, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. C. G. K. Lüder, M. Giraldo-Velásquez, M. Sendtner, and U. Gross, “Toxoplasma gondii in primary rat CNS cells: differential contribution of neurons, astrocytes, and microglial cells for the intracerebral development and stage differentiation,” Experimental Parasitology, vol. 93, no. 1, pp. 23–32, 1999. View at Publisher · View at Google Scholar · View at Scopus
  26. S. M. Lachenmaier, M. A. Deli, M. Meissner, and O. Liesenfeld, “Intracellular transport of Toxoplasma gondii through the blood-brain barrier,” Journal of Neuroimmunology, vol. 232, no. 1-2, pp. 119–130, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Skariah, M. K. McIntyre, and D. G. Mordue, “Toxoplasma gondii: determinants of tachyzoite to bradyzoite conversion,” Parasitology Research, vol. 107, no. 2, pp. 253–260, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. J. R. Radke, M. N. Guerini, M. Jerome, and M. W. White, “A change in the premitotic period of the cell cycle is associated with bradyzoite differentiation in Toxoplasma gondii,” Molecular and Biochemical Parasitology, vol. 131, no. 2, pp. 119–127, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. M. D. F. Ferreira-da-Silva, A. C. Takács, H. S. Barbosa, U. Gross, and C. G. K. Lüder, “Primary skeletal muscle cells trigger spontaneous Toxoplasma gondii tachyzoite-to-bradyzoite conversion at higher rates than fibroblasts,” International Journal of Medical Microbiology, vol. 299, no. 5, pp. 381–388, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. M. D. F. Ferreira Da Silva, H. S. Barbosa, U. Groß, and C. G. K. Lüder, “Stress-related and spontaneous stage differentiation of Toxoplasma gondii,” Molecular BioSystems, vol. 4, no. 8, pp. 824–834, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. I. J. Blader and J. P. Saeij, “Communication between Toxoplasma gondii and its host: impact on parasite growth, development, immune evasion, and virulence,” Acta Pathologica, Microbiologica et Immunologica Scandinavica, vol. 117, no. 5-6, pp. 458–476, 2009. View at Publisher · View at Google Scholar
  32. M. Soete, D. Camus, and J. F. Dubrametz, “Experimental induction of bradyzoite-specific antigen expression and cyst formation by the RH strain of Toxoplasma gondii in vitro,” Experimental Parasitology, vol. 78, no. 4, pp. 361–370, 1994. View at Publisher · View at Google Scholar · View at Scopus
  33. C. Tobin, A. Pollard, and L. Knoll, “Toxoplasma gondii cyst wall formation in activated bone marrow-derived macrophages and bradyzoite conditions,” Journal of Visualized Experiments, no. 42, Article ID e2091, 2010. View at Scopus
  34. L. M. Weiss, Y. F. Ma, P. M. Takvorian, H. B. Tanowitz, and M. Wittner, “Bradyzoite development in Toxoplasma gondii and the hsp70 stress response,” Infection and Immunity, vol. 66, no. 7, pp. 3295–3302, 1998. View at Scopus
  35. W. Bohne, J. Heesemann, and U. Gross, “Reduced replication of Toxoplasma gondii is necessary for induction of bradyzoite-specific antigens: a possible role for nitric oxide in triggering stage conversion,” Infection and Immunity, vol. 62, no. 5, pp. 1761–1767, 1994. View at Scopus
  36. B. Nare, J. J. Allocco, P. A. Liberator, and R. G. K. Donald, “Evaluation of a cyclic GMP-dependent protein kinase inhibitor in treatment of murine toxoplasmosis: gamma interferon is required for efficacy,” Antimicrobial Agents and Chemotherapy, vol. 46, no. 2, pp. 300–307, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. B. A. Fox, J. P. Gigley, and D. J. Bzik, “Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation,” International Journal for Parasitology, vol. 34, no. 3, pp. 323–331, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. W. Bohne and D. S. Roos, “Stage-specific expression of a selectable marker in Toxoplasma gondii permits selective inhibition of either tachyzoites or bradyzoites,” Molecular and Biochemical Parasitology, vol. 88, no. 1-2, pp. 115–126, 1997. View at Publisher · View at Google Scholar · View at Scopus
  39. J. R. Radke, R. G. Donald, A. Eibs et al., “Changes in the expression of human cell division autoantigen-1 influence Toxoplasma gondii growth and development,” PLoS Pathogens, vol. 2, no. 10, p. e105, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. J. R. Radke, M. S. Behnke, A. J. Mackey, J. B. Radke, D. S. Roos, and M. W. White, “The transcriptome of Toxoplasma gondii,” BMC Biology, vol. 3, article 26, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. W. Bohne, M. Holpert, and U. Gross, “Stage differentiation of the protozoan parasite Toxoplasma gondii,” Immunobiology, vol. 201, no. 2, pp. 248–254, 1999. View at Scopus
  42. U. Gross, W. Bohne, M. Soête, and J. F. Dubremetz, “Developmental differentiation between tachyzoites and bradyzoites of Toxoplasma gondii,” Parasitology Today, vol. 12, no. 1, pp. 30–33, 1996. View at Publisher · View at Google Scholar · View at Scopus
  43. J. P. J. Saeij, G. Arrizabalaga, and J. C. Boothroyd, “A cluster of four surface antigen genes specifically expressed in bradyzoites, SAG2CDXY, plays an important role in Toxoplasma gondii persistence,” Infection and Immunity, vol. 76, no. 6, pp. 2402–2410, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. S. K. Kim, A. Karasov, and J. C. Boothroyd, “Bradyzoite-specific surface antigen SRS9 plays a role in maintaining Toxoplasma gondii persistence in the brain and in host control of parasite replication in the intestine,” Infection and Immunity, vol. 75, no. 4, pp. 1626–1634, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. W. Zhang, S. K. Halonen, Y. F. Ma, M. Wittner, and L. M. Weiss, “Initial characterization of CST1, a Toxoplasma gondii cyst wall glycoprotein,” Infection and Immunity, vol. 69, no. 1, pp. 501–507, 2001. View at Publisher · View at Google Scholar · View at Scopus
  46. W. J. Sullivan Jr., J. Narasimhan, M. M. Bhatti, and R. C. Wek, “Parasite-specific eIF2 (eukaryotic initiation factor-2) kinase required for stress-induced translation control,” Biochemical Journal, vol. 380, no. 2, pp. 523–531, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. J. Narasimhan, B. R. Joyce, A. Naguleswaran et al., “Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii,” Journal of Biological Chemistry, vol. 283, no. 24, pp. 16591–16601, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. V. Pszenny, P. H. Davis, X. W. Zhou, C. A. Hunter, V. B. Carruthers, and D. S. Roos, “Targeted disruption of Toxoplasma gondii serine protease inhibitor 1 increases bradyzoite cyst formation in vitro and parasite tissue burden in mice,” Infection and Immunity, vol. 80, no. 3, pp. 1156–1165, 2012.
  49. C. Aurrecoechea, J. Brestelli, B. P. Brunk et al., “EuPathDB: a portal to eukaryotic pathogen databases,” Nucleic Acids Research, vol. 38, no. 1, Article ID gkp941, pp. D415–D419, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. B. Gajria, A. Bahl, J. Brestelli et al., “ToxoDB: an integrated Toxoplasma gondii database resource,” Nucleic Acids Research, vol. 36, no. 1, pp. D553–D556, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Bahl, P. H. Davis, M. Behnke et al., “A novel multifunctional oligonucleotide microarray for Toxoplasma gondii,” BMC Genomics, vol. 11, article 603, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. V. B. Carruthers and Y. Suzuki, “Effects of Toxoplasma gondii infection on the brain,” Schizophrenia Bulletin, vol. 33, no. 3, pp. 745–751, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. Y. Suzuki and J. S. Remington, “Toxoplasmic encephalitis in AIDS patients and experimental models for study of the disease and its treatment,” Research in Immunology, vol. 144, no. 1, pp. 66–67, 1993. View at Scopus
  54. Y. Suzuki, “Host resistance in the brain against Toxoplasma gondii,” Journal of Infectious Diseases, vol. 185, supplement 1, pp. S58–S65, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Suzuki and K. Joh, “Effect of the strain of Toxoplasma gondii on the development of Toxoplasmic encephalitis in mice treated with antibody to interferon-gamma,” Parasitology Research, vol. 80, no. 2, pp. 125–130, 1994. View at Scopus
  56. J. P. J. Saeij, J. P. Boyle, M. E. Grigg, G. Arrizabalaga, and J. C. Boothroyd, “Bioluminescence imaging of Toxoplasma gondii infection in living mice reveals dramatic differences between strains,” Infection and Immunity, vol. 73, no. 2, pp. 695–702, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. S. E. Jamieson, H. Cordell, E. Petersen, R. McLeod, R. E. Gilbert, and J. M. Blackwell, “Host genetic and epigenetic factors in toxoplasmosis,” Memorias do Instituto Oswaldo Cruz, vol. 104, no. 2, pp. 162–169, 2009. View at Scopus
  58. R. Pifer and F. Yarovinsky, “Innate responses to Toxoplasma gondii in mice and humans,” Trends in Parasitology, vol. 27, no. 9, pp. 388–393, 2011. View at Publisher · View at Google Scholar
  59. M. E. Sarciron and A. Gherardi, “Cytokines involved in Toxoplasmic encephalitis,” Scandinavian Journal of Immunology, vol. 52, no. 6, pp. 534–543, 2000. View at Publisher · View at Google Scholar · View at Scopus
  60. S. J. Parker, C. W. Roberts, and J. Alexander, “CD8+ T cells are the major lymphocyte subpopulation involved in the protective immune response to Toxoplasma gondii in mice,” Clinical and Experimental Immunology, vol. 84, no. 2, pp. 207–212, 1991. View at Scopus
  61. K. A. Jordan and C. A. Hunter, “Regulation of CD8+ T cell responses to infection with parasitic protozoa,” Experimental Parasitology, vol. 126, no. 3, pp. 318–325, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. T. H. Harris, E. H. Wilson, E. D. Tait et al., “NF-κB1 contributes to T cell-mediated control of Toxoplasma gondii in the CNS,” Journal of Neuroimmunology, vol. 222, no. 1-2, pp. 19–28, 2010. View at Publisher · View at Google Scholar · View at Scopus
  63. D. F. LaRosa, J. S. Stumhofer, A. E. Gelman et al., “T cell expression of MyD88 is required for resistance to Toxoplasma gondii,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 10, pp. 3855–3860, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. E. N. Villegas, L. A. Lieberman, N. Mason et al., “A role for inducible costimulator protein in the CD28-independent mechanism of resistance to Toxoplasma gondii,” Journal of Immunology, vol. 169, no. 2, pp. 937–943, 2002. View at Scopus
  65. E. H. Wilson, T. H. Harris, P. Mrass et al., “Behavior of parasite-specific effector CD8+ T cells in the brain and visualization of a kinesis-associated system of reticular fibers,” Immunity, vol. 30, no. 2, pp. 300–311, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. X. Wang, H. Kang, T. Kikuchi, and Y. Suzuki, “Gamma interferon production, but not perforin-mediated cytolytic activity, of T cells is required for prevention of Toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease,” Infection and Immunity, vol. 72, no. 8, pp. 4432–4438, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. X. Wang, J. Claflin, H. Kang, and Y. Suzuki, “Importance of CD8+Vβ8+ T cells in IFN-γ-mediated prevention of Toxoplasmic encephalitis in genetically resistant BALB/c mice,” Journal of Interferon and Cytokine Research, vol. 25, no. 6, pp. 338–344, 2005. View at Publisher · View at Google Scholar · View at Scopus
  68. Y. Suzuki, J. Claflin, X. Wang, A. Lengi, and T. Kikuchi, “Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii,” International Journal for Parasitology, vol. 35, no. 1, pp. 83–90, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. F. Dogruman-Al, I. Fidan, B. Celebi et al., “Cytokine profile in murine toxoplasmosis,” Asian Pacific Journal of Tropical Medicine, vol. 4, no. 1, pp. 16–19, 2011. View at Publisher · View at Google Scholar
  70. C. C. Ploix, S. Noor, J. Crane et al., “CNS-derived CCL21 is both sufficient to drive homeostatic CD4+ T cell proliferation and necessary for efficient CD4+ T cell migration into the CNS parenchyma following Toxoplasma gondii infection,” Brain, Behavior, and Immunity, vol. 25, no. 5, pp. 883–896, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Flores, R. Saavedra, R. Bautista et al., “Macrophage migration inhibitory factor (MIF) is critical for the host resistance against Toxoplasma gondii,” The FASEB Journal, vol. 22, no. 10, pp. 3661–3671, 2008. View at Publisher · View at Google Scholar
  72. M. K. Middleton, A. M. Zukas, T. Rubinstein et al., “12/15-lipoxygenase-dependent myeloid production of interleukin-12 is essential for resistance to chronic toxoplasmosis,” Infection and Immunity, vol. 77, no. 12, pp. 5690–5700, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. C. C. Chao, W. R. Anderson, S. Hu, G. Gekker, A. Martella, and P. K. Peterson, “Activated microglia inhibit multiplication of Toxoplasma gondii via a nitric oxide mechanism,” Clinical Immunology and Immunopathology, vol. 67, no. 2, pp. 178–183, 1993. View at Publisher · View at Google Scholar · View at Scopus
  74. P. K. Peterson, G. Gekker, S. Hu, and C. C. Chao, “Human astrocytes inhibit intracellular multiplication of Toxoplasma gondii by a nitric oxide-mediated mechanism,” Journal of Infectious Diseases, vol. 171, no. 2, pp. 516–518, 1995. View at Scopus
  75. S. K. Halonen, W. D. Lyman, and F. C. Chiu, “Growth and development of Toxoplasma gondii in human neurons and astrocytes,” Journal of Neuropathology and Experimental Neurology, vol. 55, no. 11, pp. 1150–1156, 1996. View at Scopus
  76. D. J. P. Ferguson and W. M. Hutchison, “An ultrastructural study of the early development and tissue cyst formation of Toxoplasma gondii in the brains of mice,” Parasitology Research, vol. 73, no. 6, pp. 483–491, 1987. View at Publisher · View at Google Scholar · View at Scopus
  77. E. H. Wilson and C. A. Hunter, “The role of astrocytes in the immunopathogenesis of Toxoplasmic encephalitis,” International Journal for Parasitology, vol. 34, no. 5, pp. 543–548, 2004. View at Publisher · View at Google Scholar · View at Scopus
  78. R. M. Andrade, M. Wessendarp, M. J. Gubbels, B. Striepen, and C. S. Subauste, “CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes,” Journal of Clinical Investigation, vol. 116, no. 9, pp. 2366–2377, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. S. K. Halonen, “Role of autophagy in the host defense against Toxoplasma gondii in astrocytes,” Autophagy, vol. 5, no. 2, pp. 268–269, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. I. Dellacasa-Lindberg, J. M. Fuks, R. B.G. Arrighi et al., “Migratory activation of primary cortical microglia upon infection with Toxoplasma gondii,” Infection and Immunity, vol. 79, no. 8, pp. 3046–3052, 2011. View at Publisher · View at Google Scholar
  81. U. Wille, M. Nishi, L. Lieberman, E. H. Wilson, D. S. Roos, and C. A. Hunter, “IL-10 is not required to prevent immune hyperactivity during memory responses to Toxoplasma gondii,” Parasite Immunology, vol. 26, no. 5, pp. 229–236, 2004. View at Publisher · View at Google Scholar · View at Scopus
  82. J. S. Stumhofer, J. S. Silver, A. Laurence et al., “Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10,” Nature Immunology, vol. 8, no. 12, pp. 1363–1371, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. J. S. Stumhofer, A. Laurence, E. H. Wilson et al., “Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system,” Nature Immunology, vol. 7, no. 9, pp. 937–945, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Villarino, L. Hibbert, L. Lieberman et al., “The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection,” Immunity, vol. 19, no. 5, pp. 645–655, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. J. Gardner and A. Ghorpade, “Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system,” Journal of Neuroscience Research, vol. 74, no. 6, pp. 801–806, 2003. View at Publisher · View at Google Scholar · View at Scopus
  86. R. T. Clark, J. Philip Nance, S. Noor, and E. H. Wilson, “T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain,” ASN Neuro, vol. 3, no. 1, Article ID e00049, pp. 1–12, 2011. View at Publisher · View at Google Scholar
  87. E. Candelario-Jalil, Y. Yang, and G. A. Rosenberg, “Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia,” Neuroscience, vol. 158, no. 3, pp. 983–994, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. T. C. Melzer, H. J. Cranston, L. M. Weiss, and S. K. Halonen, “Host cell preference of Toxoplasma gondii cysts in murine brain: a confocal study,” Journal of Neuroparasitology, vol. 1, Article ID N100505, 2010.
  89. M. Schaeffer, S. J. Han, T. Chtanova et al., “Dynamic imaging of T cell-parasite interactions in the brains of mice chronically infected with Toxoplasma gondii,” Journal of Immunology, vol. 182, no. 10, pp. 6379–6393, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. R. Gazzinelli, Y. Xu, S. Hieny, A. Cheever, and A. Sher, “Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii,” Journal of Immunology, vol. 149, no. 1, pp. 175–180, 1992. View at Scopus
  91. D. M. Israelski and J. S. Remington, “Toxoplasmic encephalitis in patients with AIDS,” Infectious Disease Clinics of North America, vol. 2, no. 2, pp. 429–445, 1988. View at Scopus
  92. P. A. Witting, “Learning capacity and memory of normal and Toxoplasma-infected laboratory rats and mice,” Zeitschrift fur Parasitenkunde, vol. 61, no. 1, pp. 29–51, 1979. View at Scopus
  93. M. Berdoy, J. P. Webster, and D. W. Mcdonald, “Fatal attraction in rats infected with Toxoplasma gondii,” Proceedings of the Royal Society B, vol. 267, no. 1452, pp. 1591–1594, 2000. View at Scopus
  94. J. P. Webster, P. H. Lamberton, C. A. Donnelly, and E. F. Torrey, “Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour,” Proceedings of The Royal Society B, vol. 273, no. 1589, pp. 1023–1030, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. A. Vyas, S. K. Kim, N. Giacomini, J. C. Boothroyd, and R. M. Sapolsky, “Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 15, pp. 6442–6447, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. J. Flegr, “Effects of Toxoplasma on human behavior,” Schizophrenia Bulletin, vol. 33, no. 3, pp. 757–760, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. J. P. Webster, “The effect of Toxoplasma gondii and other parasites on activity levels in wild and hybrid Rattus norvegicus,” Parasitology, vol. 109, no. 5, pp. 583–589, 1994. View at Scopus
  98. J. P. Webster, C. F. A. Brunton, and D. W. Macdonald, “Effect of Toxoplasma gondii upon neophobic behaviour in wild brown rats, Rattus norvegicus,” Parasitology, vol. 109, no. 1, pp. 37–43, 1994. View at Scopus
  99. P. K. House, A. Vyas, and R. Sapolsky, “Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii infected rats,” PLoS ONE, vol. 6, no. 8, Article ID e23277, 2011. View at Publisher · View at Google Scholar
  100. M. Berdoy, J. P. Webster, and D. W. Macdonald, “Parasite-altered behaviour: is the effect of Toxoplasma gondii on Rattus norvegicus specific?” Parasitology, vol. 111, no. 4, pp. 403–409, 1995. View at Scopus
  101. A. Vyas and R. Sapolsky, “Manipulation of host behaviour by Toxoplasma gondii: what is the minimum a proposed proximate mechanism should explain?” Folia Parasitologica, vol. 57, no. 2, pp. 88–94, 2010. View at Scopus
  102. M. Gulinello, M. Acquarone, J. H. Kim et al., “Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology,” Microbes and Infection, vol. 12, no. 7, pp. 528–537, 2010. View at Publisher · View at Google Scholar
  103. I. M. Ethell and D. W. Ethell, “Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets,” Journal of Neuroscience Research, vol. 85, no. 13, pp. 2813–2823, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. H. H. Stibbs, “Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice,” Annals of Tropical Medicine and Parasitology, vol. 79, no. 2, pp. 153–157, 1985. View at Scopus
  105. L. Jones-Brando, E. F. Torrey, and R. Yolken, “Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii,” Schizophrenia Research, vol. 62, no. 3, pp. 237–244, 2003. View at Publisher · View at Google Scholar · View at Scopus
  106. K. Yereli, I. C. Balcioǧlu, and A. Özbilgin, “Is Toxoplasma gondii a potential risk for traffic accidents in Turkey?” Forensic Science International, vol. 163, no. 1-2, pp. 34–37, 2006. View at Publisher · View at Google Scholar
  107. H. Wang, R. H. Yolken, P. J. Hoekstra, H. Burger, and H. C. Klein, “Antibodies to infectious agents and the positive symptom dimension of subclinical psychosis: the TRAILS study,” Schizophrenia Research, vol. 129, no. 1, pp. 47–51, 2011. View at Publisher · View at Google Scholar
  108. R. H. Yolken, E. F. Torrey, J. A. Lieberman, S. Yang, and F. B. Dickerson, “Serological evidence of exposure to Herpes Simplex Virus type 1 is associated with cognitive deficits in the CATIE schizophrenia sample,” Schizophrenia Research, vol. 128, no. 1–3, pp. 61–65, 2011. View at Publisher · View at Google Scholar
  109. D. W. Niebuhr, A. M. Millikan, D. N. Cowan, R. Yolken, Y. Li, and N. S. Weber, “Selected infectious agents and risk of schizophrenia among U.S. military personnel,” American Journal of Psychiatry, vol. 165, no. 1, pp. 99–106, 2008. View at Publisher · View at Google Scholar · View at Scopus
  110. E. F. Torrey and R. H. Yolken, “Toxoplasma gondii and schizophrenia,” Emerging Infectious Diseases, vol. 9, no. 11, pp. 1375–1380, 2003. View at Scopus
  111. B. U. Samuel, B. Hearn, D. Mack et al., “Delivery of antimicrobials into parasites,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 2, pp. 14281–14286, 2003. View at Publisher · View at Google Scholar · View at Scopus
  112. W. A. Guiguemde, A. A. Shelat, D. Bouck et al., “Chemical genetics of Plasmodium falciparum,” Nature, vol. 465, no. 7296, pp. 311–315, 2010. View at Publisher · View at Google Scholar · View at Scopus
  113. F. L. Henriquez, S. Woods, H. Cong, R. McLeod, and C. W. Roberts, “Immunogenetics of Toxoplasma gondii informs vaccine design,” Trends in Parasitology, vol. 26, no. 11, pp. 550–555, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. J. F. Dubremetz and D. J. P. Ferguson, “The role played by electron microscopy in advancing our understanding of Toxoplasma gondii and other apicomplexans,” International Journal for Parasitology, vol. 39, no. 8, pp. 883–893, 2009. View at Publisher · View at Google Scholar · View at Scopus
  115. T. Chtanova, M. Schaeffer, S. J. Han et al., “Dynamics of neutrophil migration in lymph nodes during infection,” Immunity, vol. 29, no. 3, pp. 487–496, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. I. Dellacasa-Lindberg, N. Hitziger, and A. Barragan, “Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging,” Microbes and Infection, vol. 9, no. 11, pp. 1291–1298, 2007. View at Publisher · View at Google Scholar
  117. N. Hitziger, I. Dellacasa, B. Albiger, and A. Barragan, “Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin-1 receptor signalling for host resistance assessed by in vivo bioluminescence imaging,” Cellular Microbiology, vol. 7, no. 6, pp. 837–848, 2005. View at Publisher · View at Google Scholar · View at Scopus
  118. B. John, T. H. Harris, E. D. Tait et al., “Dynamic imaging of CD8+ T cells and dendritic cells during infection with Toxoplasma gondii,” PLoS Pathogens, vol. 5, no. 7, Article ID e1000505, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. T. Chtanova, S. J. Han, M. Schaeffer et al., “Dynamics of T cell, antigen-presenting cell, and pathogen interactions during recall responses in the lymph node,” Immunity, vol. 31, no. 2, pp. 342–355, 2009. View at Publisher · View at Google Scholar · View at Scopus
  120. R. Chandramohanadas, P. H. Davis, D. P. Beiting et al., “Apicomplexan parasites co-opt host calpains to facilitate their escape from infected cells,” Science, vol. 324, no. 5928, pp. 794–797, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. D. Schlüter, M. Deckert, H. Hof, and K. Frei, “Toxoplasma gondii infection of neurons induces neuronal cytokine and chemokine production, but gamma interferon- and tumor necrosis factor-stimulated neurons fail to inhibit the invasion and growth of T. gondii,” Infection and Immunity, vol. 69, no. 12, pp. 7889–7893, 2001. View at Publisher · View at Google Scholar · View at Scopus
  122. C. A. W. Evans, M. S. Harbuz, T. Ostenfeld, A. Norrish, and J. M. Blackwell, “Nramp1 is expressed in neurons and is associated with behavioural and immune responses to stress,” Neurogenetics, vol. 3, no. 2, pp. 69–78, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. D. Schlüter, N. Kaefer, H. Hof, O. D. Wiestler, and M. Deckert-Schlüter, “Expression pattern and cellular origin of cytokines in the normal and Toxoplasma gondii-infected murine brain,” American Journal of Pathology, vol. 150, no. 3, pp. 1021–1035, 1997. View at Scopus
  124. M. Deckert, J. D. Sedgwick, E. Fischer, and D. Schlüter, “Regulation of microglial cell responses in murine Toxoplasma encephalitis by CD200/CD200 receptor interaction,” Acta Neuropathologica, vol. 111, no. 6, pp. 548–558, 2006. View at Publisher · View at Google Scholar · View at Scopus
  125. C. G. K. Lüder, C. Lang, M. Giraldo-Velasquez, M. Algner, J. Gerdes, and U. Gross, “Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA,” Journal of Neuroimmunology, vol. 134, no. 1-2, pp. 12–24, 2003. View at Publisher · View at Google Scholar · View at Scopus
  126. D. Schlúter, T. Meyer, A. Strack et al., “Regulation of microglia by CD4+ and CD8+ T cells: selective analysis in CD45-congenic normal and Toxoplasma gondii-infected bone marrow chimeras,” Brain Pathology, vol. 11, no. 1, pp. 44–55, 2001.
  127. M. Deckert-Schlüter, H. Bluethmann, N. Kaefer, A. Rang, and D. Schlüter, “Interferon-γ/receptor-mediated but not tumor necrosis factor receptor type 1- or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis,” American Journal of Pathology, vol. 154, no. 5, pp. 1549–1561, 1999. View at Scopus
  128. C. Oberdörfer, O. Adams, C. R. MacKenzie, C. J.A. De Groot, and W. Däubener, “Role of IDO activation in anti-microbial defense in human native astrocytes,” Advances in Experimental Medicine and Biology, vol. 527, pp. 15–26, 2003.
  129. S. K. Halonen and L. M. Weiss, “Investigation into the mechanism of gamma interferon-mediated inhibition of Toxoplasma gondii in murine astrocytes,” Infection and Immunity, vol. 68, no. 6, pp. 3426–3430, 2000. View at Publisher · View at Google Scholar · View at Scopus
  130. S. K. Halonen, G. A. Taylor, and L. M. Weiss, “Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP,” Infection and Immunity, vol. 69, no. 9, pp. 5573–5576, 2001. View at Publisher · View at Google Scholar · View at Scopus