Chapter 1 Abstract - Avid Science · 2016. 7. 7. · Abstract Toxoplasmic Encephalitis (TE) ......

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Encephalitis Encephalitis

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AbstractToxoplasmic Encephalitis (TE) is neurological com-

plication caused by the ubiquitous protozoan parasite, Toxoplasma gondii. This condition most frequently pre-sents in immunocompromised individuals, but can occur in other cases, including transplacental infection. Due to the high prevalence of chronic Toxoplasma infections in the general population, patients who become immunode-ficient are at risk of developing TE. We review the clinical and immunological aspects of this disease.

IntroductionEncephalitis is a relatively uncommon infection in

humans, but can have devastating effects on the patient’s health and neurological function when present. Encepha-litis has many potential etiologies, including both infec-tious and non-infectious processes. Despite significant barriers preventing pathogen access to the brain, infective causes of encephalitis include viral, bacterial, fungal, pri-on, and several parasitic pathogens [1]. One such parasitic agent is Toxoplasma gondii; since its discovery over 100 years ago [2], this parasite has been observed in post-mor-tem human studies and necropsies of other mammals, and has been considered almost a commensal organism of the CNS. In cases of immune decline and transplacental infec-tion however, T. gondii infection is anything but quiescent or commensal: instead, reactivation of disease can lead to toxoplasmic encephalitis (TE), which is lethal without treatment. This chapter covers our current clinical under-

Chapter 1

Toxoplasmic Encephalitis

Madalyn M McFarland, Maggie L Bartlett and Paul H Davis*

Department of Biology, University of Nebraska at Omaha, USA

*Corresponding Author: Paul H Davis, Department of Biology, University of Nebraska at Omaha, 6001 Dodge Street, Omaha, Nebraska 68182, USA, Tel: 402-554-3379; Fax: 402-554-3532; Email: [email protected]

First Published June 07, 2016

Copyright: © 2016 Madalyn M McFarland, Maggie L Bartlett and Paul H Davis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source.



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standing of toxoplasmic encephalitis, and reviews the im-munological interplay between this intracellular pathogen and its host’s defenses during CNS disease.

Toxoplasma gondii is capable of infecting nearly all warm-blooded animals, and is the causative agent of both toxoplasmosis and toxoplasmic encephalitis [2]. Humans typically acquire this parasite through the consumption of undercooked meat or unwashed produce, although expo-sure to contaminated water and soil have also been shown to be significant risk factors [3]. The initial infection is typically asymptomatic, and shortly after infection, the parasite transforms from its acute form, the tachyzoite, into its chronic form, the bradyzoite, via formation of cysts in brain and muscle tissues of the host. This chronic stage is maintained for the life of the host, and provides a reservoir from which the parasite can emerge when conditions become favorable (e.g. immunosuppression). Indeed, acute TE in immunocompromised individuals is more frequently due to recurrence rather than a primary infection [4]. In recent years, research on this parasitic disease has become increasingly urgent due to the associa-tion between toxoplasmic encephalitis and acquired im-munodeficiency syndrome (AIDS); 20-30% of seroposi-tive AIDS patients eventually develop TE [4,5]. Due to the implementation of Highly Active Antiretroviral Therapy (HAART) an impressive decrease in the prevalence of TE has been documented, but it remains one of the most common central nervous system (CNS) disorders seen in AIDS patients [6,7].

Clinical PresentationToxoplasma gondii is able to infect nearly every nu-

cleated cell in the human body [8]. When T. gondii in-fects the CNS, it is capable of causing four main disorders: meningoencephalitis in acutely infected immunocompe-tent hosts, encephalitis and retinochoroiditis in infants who were congenitally infected, retinochoroiditis during primary or recrudescent infection regardless of immune status, and intracerebral mass lesions or encephalitis in immunocompromised patients [9]. The presentation of these forms is largely dependent on the age at infection and immune status.

Toxoplasmic encephalitis in an immunocompetent patient is a rare event. This suggests that proper adaptive immune surveillance actively prevents the formation of TE, whether following an initial infection, or from reac-tivation of cysts. Although there are reported cases in the literature [10-14], these patients often have other predis-posing conditions, which also may complicate diagnosis and treatment. Immunocompetent patients usually pre-sent with a fever; other reported symptoms, which are less likely to be consistent between patients, are: headache, malaise, vomiting, depressed levels of consciousness, meningitis, papilledema, hemiparesis, neck rigidity, dys-arthria, convulsions, altered sensorium, rash, arthralgia, and reflex abnormalities [11].



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Congenitally infected infants fall into one of two cat-egories: infants who are symptomatic at birth and those who become symptomatic at a later age. Both have long-term effects on the infant, including sequelae on the de-veloping brain [15]. The clinical course of the infection is determined by the gestational age at which the fetus was first exposed to the parasite. Infection during the first two trimesters likely manifests as CNS malformations, such as microcephaly, polymicrogyria, and lissencephaly. In the third trimester, the fetus is more likely to develop hydro-cephalus, porencephaly, multicystic encephalomalacia, intracranial calcifications, or demyelination if they are symptomatic; the infection is often subclinical at parturi-tion if the fetus was exposed late in the pregnancy. The gestational stage also influences the likelihood of verti-cal transmission: the risk increases as the pregnancy pro-gresses from 17% at the end of the first trimester to more than 70% at the end of the last trimester [16]. If the infec-tion was subclinical at birth, effects on the fetus’s brain are still likely, often manifesting as permanent neurological and intellectual deficits. Regardless of the infant’s clini-cal status at birth, retinochoroiditis is the most common symptom of congenital toxoplasmosis, occurring any time or multiple times prior to adulthood, often resulting in unilateral or bilateral blindness.

Patients presenting with known or suspected immu-nosuppressive conditions should be considered at a high-er risk of TE and have their T. gondii antibody serostatus

identified, as positive serology is indicative of an increased risk of TE development [17]. Patients who are infected with the human immunodeficiency virus (HIV) need even more cautious monitoring; the most advanced stage, AIDS, is closely associated with the development of TE. The relationship between TE and AIDS is an important consideration for clinicians treating patients with either of these disorders, as most patients who have TE also have AIDS. Clinically, immunocompromised patients present with variable symptoms, some of the most common are: focal or nonfocal neurological effects (depending on le-sion placement), headache, confusion, fever, seizures, cho-roidoretinitis, altered mental status, and behavior changes [4]. Less commonly, patients may demonstrate extrapy-ramidal signs, movement disorders, and dementia-like symptoms. All of these symptoms can occur insidiously or can have a more acute onset. Some patients who are im-munocompromised can also present with an accompany-ing diffuse multiorgan infection, particularly patients who have recently undergone an organ transplant, while other infections are limited to the CNS, specifically the paren-chyma of the brain [9].

InfectionAfter initial ingestion of the parasite by the host, Tox-

oplasma initiates infection by contact with target cells and injection of parasite-derived, host-modifying proteins into host cell cytosol. The purpose of these proteins is to



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inhibit the cellular immune response to the parasite, and direct the assembly of the parasitophorous vacuole (PV) [18]. This PV provides an interface for the parasite to ob-tain nutrients from the host and evade destruction by in-sulating it from lysosomal or other degradative functions of the host [19].

Figure 1: Initial infection by Toxoplasma gondii. The majority of human infections are acquired through ingestion of the bradyzoite form of the parasite. The cyst undergoes transition to the rapidly di-viding tachyzoite stage during passage through the upper gastroin-testinal system. Emerging within the intestinal lumen, the parasites invade and cross host epithelial cells. Stromal cells release IL-15 and IL-18, activating natural killer cells which release IFN-γ. This leads to the recruitment and activation of the tissue-resident macrophages and dendritic cells. IL-12 is released from the activated dendritic cells, activating a parasite-specific T cell response. Parasites actively invade these recruited antigen-presenting cells and spread hematogenously throughout the body, including to the CNS.

Toxoplasma overcomes the epithelial intestinal barrier and triggers local inflammatory cytokines, in turn causing stromal cells to secrete IL-15 and IL-18 which stimulate natural killer (NK) cells and recruit inflammatory APCs (Figure 1). NK cells produce IFN-γ, recruiting and acti-vating dendritic cells at the infection site, priming them for a substantial production of IL-12 and TH1-inducing cytokines [20]. Twenty-four to forty-eight hours after oral ingestion, the patient experiences parasitemia as tachy-zoites disseminate from the intestine to the extraintestinal organs, likely via the same innate immune cells recruited to control their division and spread [21].

The process of crossing the blood-brain barrier (BBB) is an area of active research. Tachyzoite parasites exist intracellularly (mostly) and extracellularly in the blood-stream during initial acute infection, and are capable of infecting the endothelial cells of the BBB [22]. Data has shown that infected endothelial cells express altered levels of cell adhesion molecules, possibly promoting the uptake of parasites into the brain area [22]. However, advanced microscopic observations of the brain coupled with in vit-ro work suggest that the main source of Toxoplasma into the brain is via intracellular transport, likely an infected dendritic cell or other APC facilitating a so-called “Trojan horse” entry [23]. Once inside the brain, the parasite is known to infect essentially all CNS cells, including micro-glia, astrocytes, and neurons [24,25]. Approximately one month after acute infection, neurons are the predominant



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cell type harboring the now-transitioned bradyzoite cyst stage: indeed, 85% of infected brain cells are neurons [62]. However, it has been demonstrated that, although tach-yzoites can infect astrocytes and neurons equally, astro-cytes can activate IFN-γ regulated GTPases that result in up to 90% of intracellular parasites undergoing vacuolar degradation [27]. Moreover, nitric oxide intermediates are crucial for controlling chronic infection [28]. In animals without inducible nitric oxide synthase, necrotizing en-cephalitis occurs within four weeks of infection, demon-strating the importance of nitric oxide in mice surviving infection. In contrast, Toxoplasma is hypothesized to re-main in neurons due to a lack of mechanisms for parasite removal.

Brain parenchymal cells are strongly activated during initial infection of the CNS, and there is a prominent in-duction of major histocompatibility complex class I and II antigens along with ICAM-1 on cerebral endothelia, microglia, ependyma, and choroid plexus epithelia [22]. Initial CNS infection is known to recruit CD4 and CD8 T cells to the brain by VCAM-1 adhesion [22]. The in-creased entry of other inflammatory cells to the CNS is independent of ICAM-1, but depends on elevated levels of ALCAM and VCAM-1 expression in some mouse strains.

Pathology and PathogenesisIn most cases of primary infection, parasite distribu-

tion throughout the tissues and ultimately to the brain and

muscles results in subclinical, transient pathology. The de-velopment and pathogenesis of toxoplasmic encephalitis is inherently linked to the host’s immune response, and can range from asymptomatic to severe encephalitis. The asymptomatic phenotype is known to be achieved by swift activation of innate and cell-mediated immunity. In ad-dition to activation of TLR2/4 by parasite glycosylphos-phatidylinositol-anchored proteins and TLR11 activation by profilin [29], intracellular infection leads to IL-12 se-cretion by dendritic cells, macrophages, neutrophils, and monocytes [30]. The release of IL-12 then elicits high lev-els of IFN-γ to be secreted from NK cells, CD4 T cells, all of which are known to be important in parasite control [30].Once a patient is initially infected with the parasite, the cysts (bradyzoites) formed in the brain tissue remain dormant for the host’s entire life if their immune system remains intact [31]. If the immune system lapses, the para-site can revert to the tachyzoite stage through an unknown reactivating mechanism, and release rapidly dividing and infecting tachyzoites into the brain tissue, beginning the process of recurrent acute infection. Whether the parasite senses or detects an immune decline, or cysts occasionally burst to release tachyzoites into the surrounding tissues is an area of active research. Of note, poorly characterized host genetic factors are thought to be significantly more involved than parasite factors in susceptibility or resist-ance to the development of TE in murine species, how-ever the same mechanisms have not been well studied in humans [32].



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In immunocompromised hosts, TE can be caused by initial infection or recrudescence [33]. In initial infection, a localized rapid increases of cytokines in the brain results in pathological encephalitis. Alternatively, when a chronic parasitic cyst ruptures during a period of decreased im-mune system function (marked by a decrease in IFN-γ), inflammatory cells are recruited to the brain, causing damaging swelling as the parasites invade and the im-mune system attempts to mitigate the spread of infection. In AIDS patients infected with Toxoplasma, a decrease in the anti-inflammatory cytokines IL-10 and IFN-γ coincid-ing with an increase in the inflammatory cytokine TNF-α is believed to play a role in the development of TE [34]. In both initial and recrudescent infection, production of IL-12 from dendritic cells, macrophages, and neutrophils is crucial for stimulation of IFN-γ secretion to prevent or ameliorate TE [35].

During TE, large volumes of T cells and antigen-pre-senting cells flood the brain and are strongly activated, similar to other neuroinflammatory pathologies [36]. The development of TE induces lymphocyte recruitment to the CNS, and the movement of infiltrating T cells is closely associated with the infection-induced reticular system of fibers; suggesting that, unlike in other tissues which have pre-existing scaffolds for migration, specialized structures are stimulated by inflammation in the brain to guide mi-gration of T cells into this immune-privileged zone [37]. Dendritic cells are particularly activated in brains with TE, and may stimulate and intensify intracerebral T cell

responses. Previously, it was thought that the cysts were not sensed by the immune system, but more recent studies have revealed that microglia and dendritic cells are inti-mately associated with cells harboring cysts, characterized by a tight wrapping of cell bodies and dendrites around the infected cell [36].

In a severe-combined immunodeficiency mouse model, infection with T. gondii causes an increase in mac-rophage inflammatory proteins, increased levels of IL-6, IL-10, IFN-γ, TNF-α, and increased secretion of a white blood cell growth factor, granulocyte-macrophage colony-stimulating factor [38]. Administration of cytokine-neu-tralizing monoclonal antibodies leads to increased mor-tality, suggesting that these cytokines play integral roles in resisting TE development. In addition, treatment with IL-10 and IL-6 leads to increased survival time in mice, indicating that their presence can help prevent TE devel-opment [38]. When IL-10 is knocked out, mice suffer a lethal inflammatory response characterized by increased CD4 T cells, macrophages, and inflammatory cytokines in the brain [39]. This response is not seen in wild-type mice with the ability to produce IL-10, even when the parasite burden in the brain is standardized. IL-10 is an important anti-inflammatory cytokine; its absence in combination with similar parasitic burden between a knockout model and the wild-type model suggests the cause of the enceph-alitis associated with Toxoplasma infection in the mouse model is the immune response rather than the growth or



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spread of the parasite. Overall, the influx of inflammatory cytokines, the decrease in anti-inflammatory cytokines, and the increase in parasite burden cause the lethality of TE.

Mouse Strains and Varied VirulenceStudies have demonstrated that parasite strains ex-

hibit distinct levels of virulence in different strains of mice [44,45]. BALB/c mice are well known to be resistant to in-fection while C57BL/6 and CBA/Ca mice are characteris-tically susceptible [46,47]. One study identified the region of the genome in BALB/c-H-2 mice responsible for resist-ance to toxoplasmic encephalitis, located on chromosome 17 [44]. Another study found that mice with a H-2a hap-lotype are resistant while those with a H-2b haplotype are susceptible [45]. Other studies have illustrated the impor-tance of T cells and other IFN-γ producing cells in main-taining resistance in BALB/c mice [46]. In vitro studies on CBA/Ca and BALB/c mouse microglia revealed that nitric oxide, rather than IFN-γ levels, was significantly elevat-ed in BALB/c microglial cultures exposed to pathogenic stimuli [43]. Higher levels of adhesion molecule expres-sion and elevated BBB permeability have been observed in the CNS of C57BL/6 over BALB/c mice, likely contribut-ing to the major inflammatory cell infiltration seen in this more susceptible mouse strain [22].

Levels of T cell immunoglobulin mucin domain 3 (Tim-3) and programmed cell death 1 (PD-1) markers

are significantly different between mouse strains. This is particularly evident in BALB/c and C57BL/6 mice, further explaining why the two mouse strains respond differently to infection [47]. Tim-3 is identified as a TH1 response-specific marker, and plays a crucial role in CD8 T cell exhaustion in a negatively regulated TH1 response. In ad-dition, microglia and monocytes express Tim-3. PD-1 is also a marker of exhausted T cells, and has a significant effect on production of IFN-γ, TNF-α, and IL-2. A recent study found significantly increased levels of Tim-3 mRNA in the brains of C57BL/6 mice compared to BALB/c mice.PD-L1 (a PD-1 ligand) is, however, broadly expressed on antigen presenting cells, B cells, dendritic cells, mac-rophages, T cells, and non-hematopoietic cell types while PD-L2 (another PD-1 ligand) is only inducible and ex-pressed on dendritic cells and macrophages. Compared to BALB/c mice, C57BL/6 mice have elevated mRNA expres-sion levels of PD-1 and PD-L1, while PD-L2 expression was decreased after infection in both mouse strains. Thus, the role of genetic differences between strains is partially responsible for host responses in mice.

Immune Cell Mediators and their Roles in Toxoplasma Resistance

Toxoplasmic encephalitis is often seen in patients with T cell immune deficiencies, illustrating the importance of the T cell response. For example, AIDS patients’ sus-ceptibility to toxoplasmic encephalitis is dependent upon



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their T cell count [48]. In a murine model of toxoplasmic encephalitis, intravenous administration of IFN-γ can reduce inflammation in the parenchyma and perivascu-lar areas as soon as 24 hours after treatment [49]. Similar studies have been done to evaluate treating toxoplasmic encephalitis with IL-12 and other TH1 stimulators [50]. Their results have been largely supportive of the impor-tance of a TH1 response in protecting against infection as well as encephalitis.

Many other cell mediators play critical roles in resist-ance to TE. In mice that are naturally resistant to T. gondii, knocking out CD40L results in lethal disease [51], suggest-ing CD40L plays a significant role in preventing the onset of encephalitis. In another study, infection of C57BL/6 mice with T. gondii resulted in the upregulation of CD40 expression within local sites of infection and nearby lym-phoid tissue, further supporting the importance of CD40 and CD40L [51]. Five days post-infection, mice produced high levels of IL-12 and IFN-γ, which are known control-lers of apicomplexan infection; however, it was found that blocking CD40L did not significantly decrease production of these cells. This suggests that CD40L does not modu-late the key mediators of infection and that CD40L has its own role independent of IL-12 and IFN-γ. Another cell mediator, TNF-α, is upregulated post-infection in mice susceptible to TE, yet this upregulation is not seen in the brains of uninfected or non-encephalitic infected mice [52]. Other studies have shown that tumor necrosis factor

receptors p55 and p75 are important for surviving TE, as deficient mice develop fatal encephalitis, highlighting the importance of this mediator [28].

Another cell factor important for TE resistance is nu-clear factor kappa-β (NF-kβ1). In a NF-kβ1 double knock-out mouse, overall levels of T cells were increased, but fewer were found in the brain [53]. Histology in that study revealed that cell recruitment to the CNS and activation of cell cycle were not defective, but survival and prolifera-tion defects led to the reduced brain T cell population in chronic infection. A T cell-intrinsic role for NF-kβ1 is es-sential for resistance to the parasite. In NF-kβ1 null mice, a marked decrease in activated cytokine-producing CD8 T cells was documented in the spleen and brain. Although the mechanism is unclear, it is hypothesized that without NF-kβ1, the host does not have the ability to maintain suf-ficient number of parasite-specific T cells to prevent lethal infection.

Myeloid differentiation primary-response gene 88 (MyD88), an adaptor protein, has been shown to be cru-cial for signal transduction of the IL-1R/IL-18R family as well as most Toll-like receptors [54]. In a MyD88 double knockout mouse model, subjects have a defective pro-in-flammatory response, particularly in IL-12, which corre-sponds to an increased susceptibility to encephalitis [55]. Repeated exposure to Toxoplasma-derived antigen in these mice further corroborates the importance of MyD88 in Toxoplasma resistance, as these subjects cannot establish



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the integral TH1 response [55]. MyD88-dependent TLR11 participates in T. gondii resistance as well, majorly via rec-ognition of profilin derived from the pathogen. However, TLR11-null mice can survive acute toxoplasmosis [54].

Role of Different Brain Cells in Toxo-plasmic Encephalitis

Tachyzoites likely infiltrate the blood-brain barrier or enter via extravasation within innate immune cells and subsequently infect astrocytes, microglia, and neu-rons [56]. Astrocytes are glial cells in the CNS that have many functions such as supporting endothelial cells that form the BBB, providing nutrients to the CNS, maintain-ing extracellular ion balance, and repairing tissue follow-ing traumatic injuries. These cells regulate intercellular calcium which stimulates and controls neurons through calcium-dependent release of glutamate.

Astrocytes play a crucial role in reducing neuronal damage and limiting inflammation during T. gondii CNS infection. Astrocytes secrete pro-inflammatory cytokines that lead to dendritic cells physically surrounding the parasites, limiting establishment in the brain [57]. They also stimulate tumor growth factor (TGF-β) signaling, which is believed to be the main action by which astro-cytes control TE [57]. However, astrocytes may also con-tribute to the development of TE; nitric oxide can trigger activation of astrocytes and microglia cells which secrete the cytokines involved in the development of encephalitis [58]. One of the initial signs of T. gondii brain infiltration,

preceding the presence of cysts, is activation of astrocytes, which can occur as early as 10 days after initial infection [59]. Notably, infected astrocytes may well serve a critical purpose in sparing neurons through secretions leading to IL-10 production by microglial cells [60].

Another cell type that plays a critical role in patho-genesis within the CNS are microglia. Mice with TE were found to have upregulated IL-6, IL-1β, TNF-α, and induc-ible nitric oxide synthase along with increased neuronal apoptosis related to microglial involvement. In vitro, ap-optosis was significantly increased when infected neuronal cells were co-cultured with microglial cells [61]. Inhibiting microglial cells with minocycline in vivo or in vitro caused a notable decrease in microglial activation and subsequent neuronal apoptosis. Activated microglia are important in TE resistance because they produce inflammatory cy-tokines to mediate direct and indirect neuron apoptosis. In mice with TE, microglial secretion of IL-6, IL-1β and TNF-α were significantly increased. Due to minocycline’s inhibition of microglia, it also inhibits production of in-flammatory factors such as IL-6, IL-1β and TNF-α [62]. Treatment with minocycline notably decreased the release of these cytokines both in vivo and in vitro. Minocycline treatment also decreased inducible nitric oxide synthase production in microglia following infection, which is typ-ically increased in TE. The combination of decreased in-flammatory cytokines and inducible nitric oxide synthase after treatment with minocycline helped prevent TE, al-though it did not decrease the viability of the parasite or its ability to establish chronic infection [61].



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Other Considerations for TE DevelopmentNumerous factors influence whether encephalitis en-

sues after infection; these include infective parasite life stage, timing, and strain. Parasite life stage at initial in-fection, whether bradyzoite or tachyzoite, causes signifi-cantly different clinical manifestations of disease. For in-stance, transplacental infection with the tachyzoite stage causes the most distinct clinical syndrome [56]. However, most hosts are infected by ingestion of bradyzoites via carnivorism. Timing of infection can also influence de-velopment of TE. In the case of pregnancy, exposure dur-ing various times during gestation lead to different clinical outcomes. Another variable affecting the severity of infec-tion is parasite strain, which are classified as type I, II, or III. Subjects infected with type II strains are known to be susceptible to encephalitis when exposed to anti-IFN-γ, whereas subjects infected with type III parasites are not [63]. This suggests that type II parasites have greater ca-pacity to cause TE.

EpidemiologyPreviously exposed immunocompetent mothers are

very unlikely to vertically transmit a chronic T. gondii infection either in utero or via breastfeeding due to the maternal immune response elicited by aprevious chron-ically-maintained infection. Although more rare, con-genital transmission of recrudescent T. gondii infection

is almost exclusively found in patients with suppressed immune systems, particularly AIDS patients [9]. Overall, the risk of congenital infection is low over the course of the pregnancy, but for those fetuses who are infected, the likelihood of clinical sequelae manifesting during infancy and childhood is high[64]. In a study done in Brazil, ap-proximately 15,000 infants were screened for T. gondii se-rostatus, with birth prevalence estimated to be 4 cases per 10,000 live births. In that study, two-thirds of the patients experienced CNS symptoms before the age of 3. Another study followed mothers who had seroconverted during pregnancy, but received treatment, and found that 19% of the infants were subclinically infected with the parasite at parturition [65].

Patients who receive immunosuppressive therapy due to solid organ transplant are at increased risk of toxoplas-mosis. In particular, heart transplants are an important source of infection because of the formation of cysts in muscle tissues, including cardiac tissue [66]. Other solid organ transplants are less likely to transmit the infection, although there is still a possibility of infection [67]. Se-ronegative individuals who have recently received a heart transplant from a seropositive donor are at a mildly in-creased risk of TE, often associated with disseminated multisystemic infection due to the parasites originating from the transplanted heart rather than the brain of the host. In this patient population, a significant increase in mortality can be observed 5 years after transplant, likely



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because the patients are chemotherapeutically immuno-suppressed and do not have antibodies capable of eliciting a response to the parasite [68]. However, the overall risk for all heart transplants is still low because these high-risk exchanges are uncommon; a study found that T. gondii-specific serostatus was not significantly associated with adverse long-term outcomes for all heart transplant re-cipients [66].

Amongst AIDS patients, seropositivity for T. gondii antibodies is around 10-40%, and it is estimated that a third of those patients will eventually develop TE [9]. Prior to the era of HAART, the disease course of HIV was more rapid, and opportunistic diseases like TE were more com-mon. One post-HAART study found that most patients who developed TE were not compliant with HAART, or had been taking their regimens for less than 3 months [69], likely because nearly half of the study’s participants were co-diagnosed with AIDS and TE. Multiple studies have demonstrated an increase in simultaneous diag-nosis of TE and AIDS, and have correlated the patients’ lack of prophylactic treatment for TE to their previously unknown HIV status [70,71]; it is rare to see cases of TE in patients who are compliant with HAART for at least 6 months prior to a study [72], however patients who were unaware they were HIV-positive are not treated for TE prophylactically and are not on HAART, so they are at an increased risk of active disease.

DiagnosisDefinitive diagnosis of TE is only possible through

biopsy of the brain’s affected tissue; however, due to the impracticality of this test, a combination of imaging, poly-merase chain reaction (PCR) tests, and serological tests are more frequently used in practice [4]. For patients who are immunocompetent, serological testing will most often reveal both serostatus and whether the infection is acute or chronic. If IgM is the only detected antibody, then acute infection should be suspected. T. gondii-specific IgG is most often present in patients who have established chronic infections. Due to the increased occurrence of false negatives and the fluctuations of IgM and IgG titers in immunocompromised patients, their serostatus can-not be reliably tested. Because of this complication and the relative insensitivity of serology testing for T. gondii, alternative methods such as real-time quantitative PCR on the cerebral spinal fluid have been pursued. However, while some studies [73,74] have found the sensitivity of real-time qPCR to be very high, it has yet to translate into common clinical practice.

Transplant patients who were seronegative prior to transplant of an infected organ will seroconvert, and with-out prophylactic treatment, may experience severe disease [9]. Those patients who were seropositive at the time of organ receipt often experience increases in both IgM and IgG, however the infection usually remains subclinical.



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Infants who are suspected of having a congenital case of T. gondii should be tested for serostatus, however the presence of IgG antibodies may originate from maternal passive transfer or from an immune reaction generated by the infant against T. gondii [9]. IgM can also be transferred to the infant from the mother through placental leakage; however, if the infant is not producing the response, the test should demonstrate marked decreases in IgM a few weeks after birth due to the short half-life of IgM.

Imaging studies of the brain are particularly useful for distinguishing between potential diagnoses of CNS disease manifestations, all of which can present similarly to TE [4]. Magnetic Resonance Imaging (MRI) is the pre-ferred imaging method, as it has been shown to pick up lesions which Computed Tomography (CT) have missed [4,75]. The most common findings are multiple solid or cystic ring-enhanced spherical lesions, surrounding ede-ma, and space occupation. The location of the lesions may lend support to a particular differential diagnosis; TE le-sions are most often found at the cortical interface of the white and gray matter junction as well as the basal ganglia [4]. The presence of only a single lesion would support the diagnosis of a lymphoma, although TE and lympho-ma have been shown to cause both single and multiple lesions. Additionally, homogenous enhancement instead of ring enhancement of the lesion indicates possible lym-phoma. Diffuse white matter changes would support HIV dementia or progressive multifocal leukoencephalopathy

in AIDS patients, whereas diffuse changes in transplant patients may support a less common presentation of TE [9]. Immunocompetent patients are more likely to have cortical, radiating, enhancing lesions because their im-mune system is able to mount a more severe response to the parasite, causing contrast enhancement.

Distinguishing between common differential CNS di-agnoses can be challenging, if not impossible, before treat-ment because of the variability and breadth of symptoms a patient can experience [76]. In patients who have com-promised immune systems, TE is often empirically treated to reduce the risk of misdiagnosis [9]. If no effect is dem-onstrated during the first 14 days of treatment, biopsy of the affected regions may be considered in order to obtain an accurate diagnosis [76]. These samples can be tested to verify the identity of the parasite with highly specific PCR tests [9]. If a patient is treated with corticosteroids and an-tiparasitics, lymphoma will respond similarly to TE, thus discontinuation of steroids must be done with supervision in order to ensure lymphoma recurrence is caught as early as possible [17].

TreatmentThe treatment and prevention of encephalitis and

other forms of CNS toxoplasmosis are very similar due to the need for the drugs to cross the blood-brain barrier [77,78]. Without this ability, the drugs would be ineffective at suppressing the proliferation of the parasite causing the



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disorder [79]. For immunocompromised patients, com-bination therapy with pyrimethamine, sulfadiazine, and folinic acid is recommended for TE [17]. Pyrimethamine, a tetrahydrofolic acid synthesis inhibitor, is not parasite-specific and thus may also prevent the host from carrying out DNA synthesis, although to a lesser degree. In order to combat this, folinic acid, a derivative of tetrahydrofolic acid, is coadministered to avoid significant hematological toxicity [80]. Because sulfonamide-containing antimi-crobials are one of the leading causes of drug reactions, sulfadiazine, another DNA synthesis inhibitor, is often poorly tolerated [81]. In these cases, or if the patient is not responding to first-line therapy within 14 days, clindamy-cin may be substituted for sulfadiazine [17].

Problematically, patients with encephalitis often can-not take medications orally, thus causing reliance on par-enteral routes of administration. Well-studied first-line combination therapies for these patients are not currently clinically available; injectable forms of pyrimethamine and sulfadiazine are not widely available for clinical use, although clindamycin can be administered parenterally. Additional combination therapies can be considered if first-line treatment is unavailable or ineffective, including trimethoprim-sulfamethoxazole [17,78]. If acquisition of first-line antiparasitics is delayed, treatment with the more widely available trimethoprim-sulfamethoxazole should be started immediately. Due to the importance of sulfon-amide-containing compounds in the success of TE treat-

ment, it may be appropriate to attempt desensitization via an established protocol [82] in patients with reported allergies. Antiparasitic acute therapy should be adminis-tered for a minimum of 6 weeks in immunocompromised patients, with discontinuation contingent upon clinical and radiological symptom resolution. If improvement is not noted by day 14 of treatment, alternative therapies should be pursued [17]. Other complications that may be noted are mainly related to drug toxicity; patients should be monitored for side effects, particularly hematological toxicity from pyrimethamine [83,84]. Occurrence of im-mune reconstitution inflammatory syndrome, while an extremely rare event, does not change the recommended treatment regimens for TE[85].Treatment of an immu-nocompetent patient is most often similar to the primary treatment plan for immunocompromised patients [11]. Prophylactic and follow-up treatment is rarely required due to the immune system’s ability to control the growth of the bradyzoite form of the parasite.

Patients who have a history of seizures should be given anticonvulsants throughout acute therapy at minimum, with the possibility of longer-term continuation based on the individual’s symptoms, while those who lack a history of convulsions should not be given prophylactic antisei-zure treatment [17]. Additionally, for patients who have a mass effect associated with focal lesions, corticosteroid treatment should be considered to reduce intracranial pressure and edema. In these patients, careful observation



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during tapering off of corticosteroid treatment is neces-sary since CNS lymphoma responds to corticosteroid treatment similarly to TE, but may reappear when treat-ment is discontinued. However, discontinuation of cor-ticosteroids should be done as soon as possible to avoid unnecessarily prolonged immune suppression and other opportunistic infections. All patients should be placed on secondary/chronic maintenance prophylaxis to prevent relapse until or unless immune reconstitution is achieved through antiretroviral therapy [86].

Primary ProphylaxisPatients who fall into the high-risk category for the

development of TE should receive prophylactic treatment until they are cleared of their high-risk status. This group of patients includes recent seronegative heart transplant recipients who have received an organ from a seroposi-tive donor and HIV-positive patients with less than 100 CD4 cells/µl, who are seropositive for T. gondii-specific antibodies [17,87]. Patients who were seronegative upon initial diagnosis and prescribed a general prophylaxis regimen that is ineffective against T. gondii should be tested for seroconversion any time their CD4 cell count falls below 100 cells/µl. The recommended treatment for these patients is trimethoprim-sulfamethoxazole, with an alternative treatment of dapsone-pyrimethamine and fo-linic acid [17]. It is important to note that not all general opportunistic infection prophylaxis regimens prescribed

for HIV/AIDS patients have the ability to prevent TE. In particular, the antiparasitic aerosolized pentamidine is not recommended for toxoplasmosis prevention [88]. Cessation of prophylaxis for patients with CD4 cell counts above 200 cells/µl for more than 3 months is heavily sup-ported in the literature [89-93]. In these studies, most pa-tients had CD4 counts around 300 cells/µl and undetect-able levels of HIV RNA in their plasma. Discontinuation is recommended in order to reduce noncompliance with other HAART therapy and to increase the patient’s quality of life [17].

Secondary ProphylaxisAfter an acute toxoplasmic encephalitis infection, re-

gardless of when the infection was initially acquired, cysts that form in the muscle and brain tissues of the patient can still release the acute form of the parasite, the tachy-zoite. Without the protection of an immune response, the immunocompromised patient is at a high-risk of re-current infection; therefore, it is appropriate to consider chronic management for these patients [17]. Immediately after discontinuation of acute therapy, patients should be either placed on or tapered to a long-term schedule for prophylaxis. The recommended treatment is the same as the acute phase of infection, a combination of pyrimeth-amine, sulfadiazine, and folinic acid, although the dosage of each is lowered in order to increase tolerability. Alter-native therapies are also similar to those used in acute treatment, however it is important to note that while the



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recommended treatment can help prevent Pneumocystis jirovecii pneumonia (another common opportunistic in-fection), the alternative therapies do not, so additional treatments may be necessary [17]. Discontinuation of chronic maintenance treatment for TE may be considered to help increase the patient’s quality of life and HAART compliance when they have completed at least 6 months of HAART, lack any symptoms of TE, have undetectable levels of viremia, and have a CD4 lymphocyte count of more than 200 cells/µl [17,86,94]. Recurrence of infection in studies following these parameters [86] was only dem-onstrated in other opportunistic infections (Pneumocys-tis carinii pneumonia) immediately following a period of noncompliance with HAART.

Considerations for PregnancyInfants who are congenitally infected with T. gondii

are at risk of developing TE either acutely or later in life during a relapse [9]. Seronegative pregnant patients should follow general prevention recommendations in order to minimize their risk of contracting and transmitting T. gondii to the fetus transplacentally and should be continu-ously monitored during the pregnancy for signs of acute infection [95]. Except in rare cases of superinfection due to strain genetic diversity, seropositive immunocompetent patients are unlikely to vertically transmit a novel strain from secondary infection or the originally encysted strain due to immunological memory responses [96,97]. How-

ever, special consideration should be given to seropositive mothers who have HIV or AIDS. For these patients, start-ing or maintaining HAART is one of the most important ways to protect the fetus from T. gondii infection [17]. If the patient is seropositive, but does not have an active in-fection, the risks and benefits of primary prophylaxis must be weighed on an individual basis; secondary prophylaxis is recommended with the same guidelines as presented for non-pregnant patients [17]. Alternative prophylaxis in these patients carries a higher risk for the fetus, but it is still minimal compared to the risk of congenital trans-mission [98]. For those HIV-positive mothers who have recently contracted Toxoplasma gondii or are experiencing active TE, treatment is recommended to begin as soon as possible. The recommended and alternative treatment are the same or similar for nonpregnant patients and pregnant mothers after the first trimester [17]. Spiramycin, a non-Food and Drug Administration (FDA) approved drug is widely used in other countries for pregnant women with T. gondii and has been suggested to be useful for the preven-tion of congenital transmission when administered start-ing in the first trimester [99]; currently, no FDA-approved treatment options are available for women in their first trimester of pregnancy. Postnatally, congenitally infected infants should be placed on combination therapy consist-ing of pyrimethamine, sulfadiazine, and folinic acid for no less than three months due to risk of relapse, with a typi-cal course lasting 12 months [84]. It is worth noting that about half of the infants treated with this combination ex-



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perience reversible neutropenia, which is reduced when sulfadoxine is substituted for sulfadiazine. Sulfadoxine, as a long-acting sulphonamide, increases the risk of an ad-verse drug reactions, so the patient’s treatment options must be weighed on an individual basis [16].

Current ResearchToxoplasmic encephalitis is an area of continuing

research, both for diagnostic tests and additional treat-ments. Patients are currently diagnosed with TE through a combination of serology and imaging studies [9]. A re-cent study has demonstrated a new way to perform sero-logical testing through immunoglobulin polypeptide spot arrays which may be both more specific and more accu-rate [100]. Others have found more specific targets in T. gondii to amplify with PCR, increasing the specificity of the currently available test [101]. Additionally, identifying cytokines in the host responsive to modulation may lead to the prevention or better management of TE. One recent study investigated the role of the Orphan Nuclear Recep-tor TLX, a protein involved in the STAT1 pathway, which enhances immunity to T. gondii infection, potentially serving as a novel drug target against TE [102]. Another study found that pyrimidinergic receptor activation can help to control T. gondii infection in macrophages, an im-mune cell likely involved in the parasite’s hematogenous spread [103]. Altering the expression of these host factors may help the host’s immune system control the infection without directly targeting the parasite.

Other active areas of research include understanding how the parasite differentiates from its tachyzoite form to its bradyzoite form, a process thought to be tightly con-trolled by parasite gene expression [104-106]. Research on potential drug targets is fairly broad, but one of the more recently characterized target sets are the enzymes in the pantothenate synthesis pathway [107]. This study found two compounds which inhibited pantothenate enzymes specifically and which were more effective than pyrimeth-amine, the gold standard of Toxoplasma treatment, indi-cating that further development may provide additional treatment options for this parasitic disease.

ConclusionMuch exploration and growth remains in our under-

standing of the host-parasite interaction of this parasite. Cats are the definitive host of the organism, and small rodents are the primary host due to the pattern of car-nivorism between these groups. Thus, humans are a dead-end host for T. gondii, yet it has impressively developed several strategies for evading the host’s immune system and establishing lifelong infection. For a pathogen to be so long-lived and so species-unrestricted is an impressive feat and its strategies have led to increased understand-ing of the underlying biology of the neuroimmune sys-tem. However, frustration still remains in our inability to overcome the chronic infection through chemotherapy, leading to lethal reactivation disease in developed and de-veloping countries. The most promising solutions may yet



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lie in combination antiparasitic therapy coupled with im-mune enhancement.

AcknowledgementsThis report was supported by the NIH grant

GM103427 (P.H.D.) and the Nebraska Research Initiative (P.H.D.). We thank the following for their critical review of the text: Elyssa Monzingo and Harim Won.

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