Toxoplasma gondii AP2IX-4 regulates gene expression during bradyzoite development

Sherri Huang, Michael J Holmes, Joshua B Radke, Dong-Pyo Hong, Ting-Kai Liu, Michael W White,  William J Sullivan

doi: https://doi.org/10.1101/104208

http://biorxiv.org/content/early/2017/01/30/104208 

Toxoplasma gondii is a protozoan parasite of great importance to human and animal health. In the host, this obligate intracellular parasite persists as a tissue cyst form that is invisible to the immune response and unaffected by current therapies. The tissue cysts facilitate transmission through predation and give rise to chronic cycles of toxoplasmosis in immune compromised patients. Transcriptional changes accompany conversion of the rapidly replicating tachyzoites into the encysted bradyzoites, yet the mechanisms underlying these alterations in gene expression are not well-defined. Here we show that AP2IX-4 is a nuclear protein exclusively expressed in tachyzoites and bradyzoites undergoing division. Knockout of AP2IX-4 had no discernible effect on tachyzoite replication, but resulted in a reduced frequency of tissue cyst formation following alkaline stress induction, a defect that is reversible by complementation. AP2IX-4 has a complex role in regulating bradyzoite gene expression, as many bradyzoite mRNAs dramatically increased beyond normal stress-induction in AP2IX-4 knockout parasites exposed to alkaline media. The loss of AP2IX-4 also resulted in a modest virulence defect and reduced cyst burden in chronically infected mice, which was also reversed by complementation. These findings illustrate that the transcriptional mechanisms responsible for tissue cyst development operate across the intermediate life cycle from the dividing tachyzoite to the dormant bradyzoite.

Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα

PLoS Pathog. 2017 Jan 26;13(1):e1006126. doi: 10.1371/journal.ppat.1006126. eCollection 2017.

Koh HJ¹, Kim YR¹, Kim JS¹, Yun JS¹, Jang K², Yang CS¹.

Tuberculosis is a global health problem and at least one-third of the world's population is infected with Mycobacterium tuberculosis (MTB). MTB is a successful pathogen that enhances its own intracellular survival by inhibiting inflammation and arresting phago-lysosomal fusion. We previously demonstrated that Toxoplasma gondii (T. gondii) dense granule antigen (GRA) 7 interacts with TNF receptor-associated factor 6 via Myeloid differentiation primary response gene 88, enabling innate immune responses in macrophages. To extend these studies, we found that GRA7 interacts with host proteins involved in antimicrobial host defense mechanisms as a therapeutic strategy for tuberculosis. Here, we show that protein kinase C (PKC)α-mediated phosphorylation of T. gondii GRA7-I (Ser52) regulates the interaction of GRA7 with PYD domain of apoptosis-associated speck-like protein containing a carboxy-terminal CARD, which is capable of oligomerization and inflammasome activation can lead to antimicrobial defense against MTB. Furthermore, GRA7-III interacted with the PX domain of phospholipase D1, facilitating its enzyme activity, phago-lysosomal maturation, and subsequent antimicrobial activity in a GRA7-III (Ser135) phosphorylation-dependent manner via PKCα. Taken together, these results underscore a previously unrecognized role of GRA7 in modulating antimicrobial host defense mechanism during mycobacterial infection.

PMID:

28125719

DOI:

10.1371/journal.ppat.1006126

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

Proc Natl Acad Sci U S A. 2017 Jan 25. pii: 201619665. doi: 10.1073/pnas.1619665114. [Epub ahead of print]

Qin A^1,2, Lai DH³, Liu Q¹, Huang W^2,4, Wu YP³, Chen X^2,4, Yan S^2,4, Xia H⁴, Hide G^5,6, Lun ZR^7,5,6, Ayala FJ⁸, Xiang AP^9,4,10.

Mesenchymal stromal cells (MSCs) have recently been shown to play important roles in mammalian host defenses against intracellular pathogens, but the molecular mechanism still needs to be clarified. We confirmed that human MSCs (hMSCs) prestimulated with IFN-γ showed a significant and dose-dependent ability to inhibit the growth of two types of Toxoplasma gondii [type I RH strain with green fluorescent proteins (RH/GFP) or type II PLK strain with red fluorescent proteins (PLK/RED)]. However, in contrast to previous reports, the anti-T. gondii activity of hMSCs was not mediated by indoleamine 2,3-dioxygenase (IDO). Genome-wide RNA sequencing (RNA-seq) analysis revealed that IFN-γ increased the expression of the p65 family of human guanylate-binding proteins (hGBPs) in hMSCs, especially hGBP1. To analyze the functional role of hGBPs, stable knockdowns of hGBP1, -2, and -5 in hMSCs were established using a lentiviral transfection system. hGBP1 knockdown in hMSCs resulted in a significant loss of the anti-T. gondii host defense property, compared with hMSCs infected with nontargeted control sequences. hGBP2 and -5 knockdowns had no effect. Moreover, the hGBP1 accumulation on the parasitophorous vacuole (PV) membranes of IFN-γ-stimulated hMSCs might protect against T. gondii infection. Taken together, our results suggest that hGBP1 plays a pivotal role in anti-T. gondii protection of hMSCs and may shed new light on clarifying the mechanism of host defense properties of hMSCs.

KEYWORDS:

human stem cells; in vitro cultivation; innate immunity; parasitic protozoan

PMID:

28123064

DOI:

10.1073/pnas.1619665114

Toxoplasma gondii induces autophagy and apoptosis in human umbilical cord mesenchymal stem cells via down-regulation of Mcl-1

Cell Cycle. 2017 Jan 23:0. doi: 10.1080/15384101.2017.1281484. [Epub ahead of print]

Chu JQ^1,2, Jing KP¹, Gao X¹, Li P¹, Huang R¹, Niu YR², Yan SQ¹, Kong JC², Yu CY³, Shi G⁴, Fan YM⁴, Lee YH⁵, Zhou Y³, Quan JH³.

Autophagy and apoptosis are critical for controlling Toxoplasma gondii (T. gondii) infection. T. gondii infection during pregnancy can damage the fetus and cause birth defects; however, the molecular mechanisms of this process are poorly understood. This study aims to determine the activities of autophagy and apoptosis as well as their regulatory mechanisms during T. gondii infection by using human umbilical cord mesenchymal stem cells (hUC-MSCs) as a model of congenital diseases. LC3B, a hallmark protein of autophagy was incrementally up-regulated with the infection duration, whereas p62 was down-regulated in T. gondii-infected hUC-MSCs. Concurrent to this result, the invasion of T. gondii into hUC-MSCs increased in a time-dependent manner. The expression levels of Bcl-2 family proteins including Bcl-2, Bcl-xL, Bim, Bax, Bid and Bak were not altered; however, Mcl-1 levels in hUC-MSCs were dramatically decreased upon T. gondii infection. In addition, at 24 h post-infection, cleaved PARP and cleaved caspase-3 protein levels were elevated in hUC-MSCs. Importantly, Mcl-1 overexpression reduced the levels of autophagy- and apoptosis-related proteins in T. gondii-infected hUC-MSCs. Mcl-1 proteins were primarily expressed in the fraction containing mitochondria and strongly interacted with Beclin-1 under normal conditions; however, these interactions were remarkably attenuated by T. gondii infection. These results suggest that mitochondrial Mcl-1 is an essential signaling mediator regulating the activation of autophagy and apoptosis during T. gondii infection.

KEYWORDS:

Beclin-1; Mcl-1; Toxoplasma gondii; apoptosis; autophagy; cell death; umbilical cord mesenchymal stem cell

PMID:

28112581

DOI:

10.1080/15384101.2017.1281484

Surface attachment, promoted by the actomyosin system of Toxoplasma gondii is important for efficient gliding motility and invasion

BMC Biol. 2017 Jan 18;15(1):1. doi: 10.1186/s12915-016-0343-5.

Whitelaw JA¹, Latorre-Barragan F¹, Gras S¹, Pall GS¹, Leung JM^2,3, Heaslip A⁴, Egarter S¹, Andenmatten N¹, Nelson SR⁴, Warshaw DM⁴, Ward GE³, Meissner M⁵.

BACKGROUND:

Apicomplexan parasites employ a unique form of movement, termed gliding motility, in order to invade the host cell. This movement depends on the parasite's actomyosin system, which is thought to generate the force during gliding. However, recent evidence questions the exact molecular role of this system, since mutants for core components of the gliding machinery, such as parasite actin or subunits of the MyoA-motor complex (the glideosome), remain motile and invasive, albeit at significantly reduced efficiencies. While compensatory mechanisms and unusual polymerisation kinetics of parasite actin have been evoked to explain these findings, the actomyosin system could also play a role distinct from force production during parasite movement.

RESULTS:

In this study, we compared the phenotypes of different mutants for core components of the actomyosin system in Toxoplasma gondii to decipher their exact role during gliding motility and invasion. We found that, while some phenotypes (apicoplast segregation, host cell egress, dense granule motility) appeared early after induction of the act1 knockout and went to completion, a small percentage of the parasites remained capable of motility and invasion well past the point at which actin levels were undetectable. Those act1 conditional knockout (cKO) and mlc1 cKO that continue to move in 3D do so at speeds similar to wildtype parasites. However, these mutants are virtually unable to attach to a collagen-coated substrate under flow conditions, indicating an important role for the actomyosin system of T. gondii in the formation of attachment sites.

CONCLUSION:

We demonstrate that parasite actin is essential during the lytic cycle and cannot be compensated by other molecules. Our data suggest a conventional polymerisation mechanism in vivo that depends on a critical concentration of G-actin. Importantly, we demonstrate that the actomyosin system of the parasite functions in attachment to the surface substrate, and not necessarily as force generator.

KEYWORDS:

Actin; Apicomplexa; Attachment; Host cell invasion; Membrane flow; Motility; Myosin; Toxoplasma

PMID:

28100223

DOI:

10.1186/s12915-016-0343-5

The Effect of Fluphenazine and Thioridazine on Toxoplasma gondii In Vivo

Iran J Parasitol. 2016 Apr-Jun;11(2):226-231.

Saraei M¹, Ghaderi Y², Mosavi T², Shahnazi M¹, Nassiri-Asl M³, Jahanihashemi H⁴.

Author information

Abstract

BACKGROUND:

Toxoplasma gondii is the most common parasite causing latent cerebral infections in human. It has been shown that some anti-psychotic drugs are able to inhibit the proliferation of the parasite in in vitro study. There is very limited data regarding the inhibitory effect of anti-psychotics on Toxoplasma in in vivo. In this study, we evaluated anti-Toxoplasma activity of fluphenazine and thioridazine drugs on T. gondii in mice.

METHODS:

Mice were divided into six groups: Control, sesame as vehicle, thioridazine 10 mg/kg, thioridazine 20 mg/kg, fluphenazine 0.06 mg/kg and fluphenazine 0.6 mg/kg. They were inoculated intraperitoneally with brain suspension containing tissue cysts of T. gondii Tehran strain. Two months after inoculation, the number of cysts in crushed smears of mice brain were counted microscopically and considered as an indicator of anti-Toxoplasma activity. This work has conducted in Qazvin, central Iran, 2014.

RESULTS:

Our study showed that fluphenazine and thioridazine could not significantly inhibit the brain cystogenesis of T. gondii in mice. However, the number of brain cysts was less at higher dose compared to lower doses for both drugs.

CONCLUSION:

Further studies need to clear the mechanism of different structure of anti-psychotic drugs on activity of Toxoplasma.

KEYWORDS:

Brain cysts; Fluphenazine; In vivo; Thioridazine; Toxoplama gondii

PMID:

 

28096857

Acetylcholinesterase Inhibitor Improves Learning and Memory Impairment Induced by Toxoplasma gondii Infection

Iran J Parasitol. 2016 Apr-Jun;11(2):177-185.

Mahmoudvand H¹, Sheibani V², Keshavarz H³, Shojaee S³, Esmaeelpour K², Ziaali N⁴.

Author information

Abstract

BACKGROUND:

Here, we established the mouse models of chronic toxoplasmosis by T. gondii Tehran strain to provide a good understanding about defining the possible association between T. gondii exposure and learning and memory impairments. Moreover, as secondary objective of the present study, we hypothesized whether administration of an acetylcholinesterase (AChE) inhibitor could reduce learning and memory impairments induced by T. gondii infection.

METHODS:

Twenty-four male BALB/c mice were used to establishment of latent toxoplasmosis. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from Tehran strain of T. gondii. Donepezil (2 mg/kg) an AChE inhibitor to treat Alzheimer disease was injected intraperitoneally once a day for two weeks starting from post-infection day 90. Morris water maze (MWM) task was used to assay spatial learning and short term spatial memory in all groups. One-way ANOVA with Tukey's post-hoc test was used to assess differences between experimental groups. P0.05 was considered statistically significant.

RESULTS:

Toxoplasma infection impaired spatial leaning and short term spatial memory of the infected BALB/c mice, whereas donepezil, an AChE inhibitor, improved impairments induced by Toxoplasma infection.

CONCLUSION:

T. gondii infection through increasing AChE reduces the level of Acetylcholine (Ach) and consequently affects learning and memory activity in infected hosts, whereas, donepezil as an AChE inhibitor improves these impairments by restoring ACh levels at synapses of neurons in brain.

KEYWORDS:

Donepezil; Maze learning; Memory; Spatial learning; Toxoplasma gondii; Toxoplasmosis

PMID:

 

28096851

Assessment of the Effects of Extremely Low Frequency Electromagnetic Fields on Toxoplasma gondii

Iran J Parasitol. 2016 Apr-Jun;11(2):159-167.

Ozlem-Caliskan S¹, Ertabaklar H², Bilgin MD³, Ertug S².

Author information

Abstract

BACKGROUND:

The effects of extremely low frequency electromagnetic fields (ELF-EMF) on Toxoplasma gondii have not been explained yet. The aim of this study was to assess the possible effects of ELF-EMF on growth, survival time and viability of Toxoplasma gondii. In addition, the life span of Toxoplasma infected animals was investigated.

METHODS:

Sixty adult male BALB/c mice were used for in vivo and in vivo experiments in Laboratory of Biopyhsics and Parasitology of Medical Faculty, Adnan Menderes University, Turkey, in 2010. During in vivo experiments, pulsed and continuous EMFs were applied for 5 d to the infected mice. During in vivo experiments, pulsed and continuous EMF was applied to the tachyzoites within peritoneal exudates for 8 h/d at 4 °C and the tachyzoites were then injected to mice. In both experiments, the number of T. gondii in peritoneal exudates was counted and T. gondii protein bands patterns were investigated with polyacrylamide gel electrophoresis and Western Blotting.

RESULTS:

Pulsed and continuous EMF exposure reduced the number of T. gondii tachyzoites in comparison to controls. However, no statistically significant differences were observed at the patterns of protein bands among the samples.

CONCLUSION:

EMF exposure induces a decrease in the number of T. gondii. Further studies are required to understand the mechanism of EMF on intracellular parasites.

KEYWORDS:

Electromagnetic field; Mice; Polyacrylamide gel electrophoresis; Toxoplasma gondii; Western Blotting

PMID:

 

28096849

Production of IL-1β and Inflammasome with Up-Regulated Expressions of NOD-Like Receptor Related Genes in Toxoplasma gondii-Infected THP-1 Macrophages

Korean J Parasitol. 2016 Dec;54(6):711-717. doi: 10.3347/kjp.2016.54.6.711. Epub 2016 Dec 31.

Chu JQ¹, Shi G², Fan YM², Choi IW³, Cha GH³, Zhou Y⁴, Lee YH³, Quan JH⁴.

Author information

Abstract

Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1β. To elucidate the role of inflammasome components in T. gondii-infected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine IL-1β secretion. The results revealed a significant upregulation of IL-1β after T. gondii infection. T. gondii infection also upregulated the expression of inflammasome sensors, including NLRP1, NLRP3, NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and NAIP, in a time-dependent manner. The infection also upregulated inflammasome adaptor protein ASC and caspase-1 mRNA levels. From this study, we newly found that T. gondii infection regulates NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and neuronal apoptosis inhibitor protein (NAIP) gene expressions in THP-1 macrophages and that the role of the inflammasome-related genes may be critical for mediating the innate immune responses to T. gondii infection.

KEYWORDS:

THP-1 macrophage; Toxoplasma gondii; inflammasome; nucleotide-binding oligomerization domain (NOD)-like receptor (NLR); qRT-PCR

PMID:

 

28095655

 

DOI:

 

10.3347/kjp.2016.54.6.711

CCAAT/Enhancer-Binding Protein β Mediates the Killing of Toxoplasma gondii by Inducing Autophagy in Nonhematopoietic Cells

DNA Cell Biol. 2017 Jan 16. doi: 10.1089/dna.2016.3434. [Epub ahead of print]

Yu Y¹, Zhao N², An J³, Zhang X⁴.

Autophagy is a main defense strategy by which infected host cells can virtually induce the killing of parasite, including Toxoplasma gondii. However, the regulatory mechanisms of autophagy in T. gondii-infected nonhematopoietic cells are still unknown. Emerging evidence indicates that CCAAT/enhancer-binding protein β (C/EBP β) is associated with the regulation of autophagy. Herein, we hypothesized that C/EBP β plays roles in inducing autophagy in nonhematopoietic cells. Expression of C/EBP β was aberrantly regulated in endothelial cells and retinal pigment epithelial cells challenged by T. gondii. Inhibition of C/EBP β reduced the killing of T. gondii in nonhematopoietic cells, whereas C/EBP β overexpression resulted in the enhancement of killing of T. gondii as well as the increase in autophagy in infected cells. Furthermore, the mammalian target of rapamycin (mTOR) activation was found to be reduced by C/EBP β overexpression, but increased by C/EBP β inhibition. The increase in T. gondii killing induced by C/EBP β overexpression was blocked by the mTOR activator phosphatidic acid and was increased by the inhibitor AZD8055. In conclusion, we demonstrate that C/EBP β expression is increased in nonhematopoietic cells infected by T. gondii, resulting in the activation of autophagy in host cells by inhibiting mTOR pathway.

KEYWORDS:

C/EBP β; T. gondii; autophagy; killing; mTOR; nonhematopoietic cells

PMID:

28092463

DOI:

10.1089/dna.2016.3434

Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis

Joshua B Radke, Danielle Worth, Dong-Pyo Hong, Sherri Huang, William J Sullivan Jr, Emma H Wilson, Michael White

doi: https://doi.org/10.1101/100628

Abstract

Bradyzoite differentiation is marked by major changes in gene expression resulting in a parasite that expresses a new repertoire of surface antigens hidden inside a modified parasitophorous vacuole called the tissue cyst. The factors that control this important life cycle transition are not well understood. Here we describe an important Toxoplasma repressor mechanism controlling bradyzoite differentiation that operates exclusively in the tachyzoite stage. The ApiAP2 factor, AP2IV-4, is a nuclear factor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle and absent from the bradyzoite. Remarkably, deletion of the AP2IV-4 locus resulted in the increased expression of bradyzoite mRNAs in replicating tachyzoites and in two different genetic lineages, we confirmed the misexpression of tissue cyst wall components (e.g. BPK1, MCP4, CST1) and the bradyzoite surface antigen SRS9 in the tachyzoite stage. In the murine animal model, the loss of AP2IV-4 had profound biological consequences. Prugniaud strain parasites lacking AP2IV-4 were unable to form tissue cysts in brain tissue and the absence of this factor also recruited a potent immune response characterized by increases inflammatory monocytes, IFN-γ and higher numbers of both CD8+ and CD4+ T-cells. Altogether these results indicate that suppression of bradyzoite antigens by AP2IV-4 during acute infection is required for Toxoplasma to establish a chronic infection in the immune-competent host.

A human proteome array approach to identifying key host proteins targeted by Toxoplasma kinase ROP18

Mol Cell Proteomics. 2017 Jan 13. pii: mcp.M116.063602. doi: 10.1074/mcp.M116.063602. [Epub ahead of print]

Yang Z1, Hou Y1, Hao T1, Rho HS2, Wan J2, Luan Y1, Gao X1, Yao J1, Pan A1, Xie Z1, Qian J2, Liao W1, Zhu H2, Zhou X3.

Author information

Abstract

Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty-eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1 were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and providing new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface.

Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

KEYWORDS: 

Kinases*; Microbiology; Pathogens; Protein array; Protein-Protein Interactions*; host-pathogen interaction; proteome array

PMID:

 

28087594

 

DOI:

 

10.1074/mcp.M116.063602

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets

BMC Infect Dis. 2017 Jan 13;17(1):66. doi: 10.1186/s12879-016-2159-x.

Rb-Silva R1,2, Nobrega C1,2, Reiriz E3, Almeida S3, Sarmento-Castro R1,2,3, Correia-Neves M4,5, Horta A1,2,3.

Author information

Abstract

BACKGROUND: 

HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed.

CASE PRESENTATION: 

A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4+ T cells and higher percentage of activated CD4+ T cells at HAART initiation. The percentage of memory CD4+ T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8+ T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset.

CONCLUSION: 

Although both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition.

KEYWORDS: 

Human immunodeficiency virus; Immune reconstitution inflammatory syndrome; Regulatory T cells; T cell subsets; Toxoplasmosis

PMID:

 

28086758

 

DOI:

 

10.1186/s12879-016-2159-x

A critical assessment of the association between postnatal toxoplasmosis and epilepsy in immune-competent patients

Eur J Clin Microbiol Infect Dis. 2017 Jan 12. doi: 10.1007/s10096-016-2897-0. [Epub ahead of print]

Uzorka JW1,2, Arend SM3.

Author information

Abstract

While postnatal toxoplasmosis in immune-competent patients is generally considered a self-limiting and mild illness, it has been associated with a variety of more severe clinical manifestations. The causal relation with some manifestations, e.g. myocarditis, has been microbiologically proven, but this is not unequivocally so for other reported associations, such as with epilepsy. We aimed to systematically assess causality between postnatal toxoplasmosis and epilepsy in immune-competent patients. A literature search was performed. The Bradford Hill criteria for causality were used to score selected articles for each component of causality. Using an arbitrary but defined scoring system, the maximal score was 15 points (13 for case reports). Of 704 articles, five case reports or series and five case-control studies were selected. The strongest evidence for a causal relation was provided by two case reports and one case-control study, with a maximal causality score of, respectively, 9/13, 10/13 and 10/15. The remaining studies had a median causality score of 7 (range 5-9). No selection bias was identified, but 6/10 studies contained potential confounders (it was unsure whether the infection was pre- or postnatal acquired, or immunodeficiency was not specifically excluded). Based on the evaluation of the available literature, although scanty and of limited quality, a causal relationship between postnatal toxoplasmosis and epilepsy seems possible. More definite proof requires further research, e.g. by performing Toxoplasma serology in all de novo epilepsy cases.

PMID:

 

28083719

 

DOI:

 

10.1007/s10096-016-2897-0