Chronic infection of Toxoplasma gondii downregulates miR-132 expression in multiple brain regions in a sex-dependent manner

Parasitology. 2014 Oct 29:1-10. [Epub ahead of print]

 

Li Y¹, Kannan G², Pletnikov MV², Yolken RH¹, Xiao J¹.

 

MicroRNA-132 (miR-132) has been demonstrated to affect multiple neuronal functions and its dysregulation is linked to several neurological disorders. We previously showed that acute Toxoplasma gondii infection induces miR-132 expression both in vitro and in vivo. To investigate the impact of chronic infection on miR-132, we infected mice with T. gondii PRU strain and performed assessment 5 months later in six brain regions (cortex, hypothalamus, striatum, cerebellum, olfactory bulb and hippocampus) by qPCR. We found that while acute infection of T. gondii increases the expression of miR-132, chronic infection has the opposite effect. The effect varied amongst different regions of the brain and presented in a sex-dependent manner, with females exhibiting more susceptibility than males. MiR-132 and brain-derived neurotrophic factor (BDNF, an inducer of miR-132) were not co-varies in the brain areas of infected mice. T. gondii DNA/RNA was found in all tested brain regions and a selective tropism towards the hippocampus, based on bradyzoite density, was observed in both males and females. However, the expressions of miR-132 or BDNF were poorly reflected by the density of T. gondii in brain areas. Our findings highlight the importance of investigating the miR-132-mediated neuronal function in mice infected with T. gondii.

PMID:

25351997

[PubMed - as supplied by publisher]

Cerebral and ocular toxoplasmosis related with IFN-γ, TNF-α, and IL-10 levels

Front Microbiol. 2014 Oct 13;5:492. doi: 10.3389/fmicb.2014.00492. eCollection 2014.

 

Meira CS¹, Pereira-Chioccola VL¹, Vidal JE², de Mattos CC³, Motoie G¹, Costa-Silva TA¹, Gava R¹, Frederico FB⁴, de Mattos LC³; Toxoplasma Groups.

 

This study analyzed the synthesis of Interferon gamma (IFN-γ), Tumor Necrosis Factor alpha (TNF-α), and Interleukin 10 (IL-10) in chronically infected patients which developed the symptomatic disease as cerebral or ocular toxoplasmosis. Blood from 61 individuals were divided into four groups: Cerebral toxoplasmosis/AIDS patients (CT/AIDS group) (n = 15), ocular toxoplasmosis patients (OT group) (n = 23), chronic toxoplasmosis individuals (CHR group) (n = 13) and healthy individuals (HI group) (n = 10). OT, CHR, and HI groups were human immunodeficiency virus (HIV) seronegative. The diagnosis was made by laboratorial (PCR and ELISA) and clinical subjects. For cytokine determination, peripheral blood mononuclear cells (PBMC) of each patient were isolated and stimulated in vitro with T. gondii antigen. IFN-γ, TNF-α, and IL-10 activities were determined by ELISA. Patients from CT/AIDS and OT groups had low levels of IFN-γ when were compared with those from CHR group. These data suggest the low resistance to develop ocular lesions by the low ability to produce IFN-γ against the parasite. The same patients, which developed ocular or cerebral toxoplasmosis had higher TNF-α levels than CHR individuals. High TNF-α synthesis contribute to the inflammatory response and damage of the choroid and retina in OT patients and in AIDS patients caused a high inflammatory response as the TNF-α synthesis is not affected since monocytes are the major source this cytokine in response to soluble T. gondii antigens. IL-10 levels were almost similar in CT/AIDS and OT patients but low when compared with CHR individuals. The deviation to Th2 immune response including the production of anti-inflammatory cytokines, such as IL-10 may promote the parasite's survival causing the tissue immune destruction. IL-10 production in T. gondii-infected brains may support the persistence of parasites as down-regulating the intracerebral immune response. All these indicate that OT and CT/AIDS patients produced low levels of IL-10 (Th2 response) and IFN-γ (Th1 response). They produced high TNF-α suggesting a high inflammatory response triggered by the parasite.

KEYWORDS:

Toxoplasma gondii; cerebral toxoplasmosis and AIDS; cytokines; immune response; ocular toxoplasmosis

PMID:

25352834

[PubMed]

Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii

J Immunol. 2014 Oct 29. pii: 1401629. [Epub ahead of print]

 

Oksanen A¹, Aittomäki S¹, Jankovic D², Ortutay Z¹, Pulkkinen K¹, Hämäläinen S¹, Rokka A³, Corthals GL⁴, Watford WT⁵, Junttila I⁶, O'Shea JJ⁷, Pesu M⁸.

 

The proprotein convertase subtilisin/kexin enzymes proteolytically convert immature proproteins into bioactive molecules, and thereby they serve as key regulators of cellular homeostasis. The archetype proprotein convertase subtilisin/kexin, FURIN, is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in Th1 cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGF-β1 in vivo, but FURIN's role in cell-mediated immunity and Th polarization has remained elusive. In this article, we show that T cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii, and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4R subunit α on cell surface, sensitized IL-4/STAT6 signaling, and a propensity to polarize toward the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass spectrometry, we further identify an association with a cytoskeleton modifying Ras-related C3 botulinum toxin substrate/dedicator of cytokinesis 2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to downregulate IL-4R subunit α cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance.
Copyright © 2014 by The American Association of Immunologists, Inc.

PMID:

25355923

[PubMed - as supplied by publisher]

The role of hormones on Toxoplasma gondii infection: a systematic review

Front Microbiol. 2014 Oct 9;5:503. doi: 10.3389/fmicb.2014.00503. eCollection 2014.

 

Galván-Ramírez Mde L, Gutiérrez-Maldonado AF, Verduzco-Grijalva F, Jiménez JM.

 

BACKGROUND:

Toxoplasma gondii is the causal agent of toxoplasmosis in which one third of the world's population has been infected. In pregnant women, it may cause abortion and severe damage to the fetal central nervous system. During pregnancy, the prevalence of toxoplasmosis increases throughout the second and third quarter of gestation, simultaneously progesterone and 17β-estradiol also increase. Thus, it has been suggested that these hormones can aggravate or reduce parasite reproduction. The aim of this study was reviewing the relationship between hormones and infection caused by T. gondii in several experimental animal models and humans, focused mainly on: (a) congenital transmission, (b) parasite reproduction, (c) strain virulence, (d) levels of hormone in host induced by T. gondii infection, and (e) participation of hormone receptors in T. gondii infection. Are the hormones specific modulators of T. gondii infection? A systematic review methodology was used to consult several databases (Pub Med, Lilacs, Medline, Science direct, Scielo, Ebsco, Sprinker, Wiley, and Google Scholar) dated from September, 2013 to March, 2014.

RESULTS:

Thirty studies were included; eight studies in humans and 22 in animals and cell cultures. In the human studies, the most studied hormones were testosterone, progesterone, prolactin, and 17β-estradiol. Type I (RH and BK) and Type II (Prugniaud, SC, ME49, T45, P78, and T38) were the most frequent experimental strains.

CONCLUSIONS:

Thirty-five years have passed since the first studies regarding T. gondii infection and its relationship with hormones. This systematic review suggests that hormones modulate T. gondii infection in different animal models. However, given that data were not comparable, further studies are required to determine the mechanism of hormone action in the T. gondii infectious process.

KEYWORDS:

Toxoplasma; Toxoplasma infection; no steroid hormones; steroids hormones; toxoplasmosis

PMID:

25346725

[PubMed]

Effects of Latent Toxoplasmosis on Autoimmune Thyroid Diseases in Pregnancy

PLoS One. 2014 Oct 28;9(10):e110878. doi: 10.1371/journal.pone.0110878. eCollection 2014

 

Kaňková S¹, Procházková L¹, Flegr J¹, Calda P², Springer D³, Potluková E⁴.

 

BACKGROUND:

Toxoplasmosis, one of the most common zoonotic diseases worldwide, can induce various hormonal and behavioural alterations in infected hosts, and its most common form, latent toxoplasmosis, influences the course of pregnancy. Autoimmune thyroid diseases (AITD) belong to the well-defined risk factors for adverse pregnancy outcomes. The aim of this study was to investigate whether there is a link between latent toxoplasmosis and maternal AITD in pregnancy.

METHODS:

Cross-sectional study in 1248 consecutive pregnant women in the 9-12th gestational weeks. Serum thyroid-stimulating hormone (TSH), thyroperoxidase antibodies (TPOAb), and free thyroxine (FT4) were assessed by chemiluminescence; the Toxoplasma status was detected by the complement fixation test (CFT) and anti-Toxoplasma IgG enzyme-linked immunosorbent assay (ELISA).

RESULTS:

Overall, 22.5% of the women were positive for latent toxoplasmosis and 14.7% were screened positive for AITD. Women with latent toxoplasmosis had more often highly elevated TPOAb than the Toxoplasma-negative ones (p = 0.004), and latent toxoplasmosis was associated with decrease in serum TSH levels (p = 0.049). Moreover, we found a positive correlation between FT4 and the index of positivity for anti-Toxoplasma IgG antibodies (p = 0.033), which was even stronger in the TPOAb-positive Toxoplasma-positive women, (p = 0.014), as well as a positive correlation between FT4 and log2 CFT (p = 0.009).

CONCLUSIONS:

Latent toxoplasmosis was associated with a mild increase in thyroid hormone production in pregnancy. The observed Toxoplasma-associated changes in the parameters of AITD are mild and do not seem to be clinically relevant; however, they could provide new clues to the complex pathogenesis of autoimmune thyroid diseases.

PMID:

25350671

[PubMed - as supplied by publisher]

Functional Analysis of Rhomboid Proteases during Toxoplasma Invasion

MBio. 2014 Oct 21;5(5). pii: e01795-14. doi: 10.1128/mBio.01795-14.

 

Shen B¹, Buguliskis JS¹, Lee TD¹, Sibley LD².

 

Host cell invasion by Toxoplasma gondii and other apicomplexan parasites requires transmembrane adhesins that mediate binding to receptors on the substrate and host cell to facilitate motility and invasion. Rhomboid proteases (ROMs) are thought to cleave adhesins within their transmembrane segments, thus allowing the parasite to disengage from receptors and completely enter the host cell. To examine the specific roles of individual ROMs during invasion, we generated single, double, and triple knockouts for the three ROMs expressed in T. gondii tachyzoites. Analysis of these mutants demonstrated that ROM4 is the primary protease involved in adhesin processing and host cell invasion, whereas ROM1 or ROM5 plays negligible roles in these processes. Deletion of ROM4 blocked the shedding of adhesins such as MIC2 (microneme protein 2), causing them to accumulate on the surface of extracellular parasites. Increased surface adhesins led to nonproductive attachment, altered gliding motility, impaired moving junction formation, and reduced invasion efficiency. Despite the importance of ROM4 for efficient invasion, mutants lacking all three ROMs were viable and MIC2 was still efficiently removed from the surface of invaded mutant parasites, implying the existence of ROM-independent mechanisms for adhesin removal during invasion. Collectively, these results suggest that although ROM processing of adhesins is not absolutely essential, it is important for efficient host cell invasion by T. gondii.

IMPORTANCE:

Apicomplexan parasites such as Toxoplasma gondii express surface proteins that bind host cell receptors to aid invasion. Many of these adhesins are subject to cleavage by rhomboid proteases (ROMs) within their transmembrane segments during invasion. Previous studies have demonstrated the importance of adhesin cleavage for parasite invasion and proposed that the ROMs responsible for processing would be essential for parasite survival. In T. gondii, ROM5 was thought to be the critical ROM for adhesin shedding due to its robust protease activity in vitro and posterior localization on the parasite surface. Here, we knocked out all three ROMs in T. gondii tachyzoites and found that ROM4, but not ROM5, was key for adhesin cleavage. However, none of the ROMs individually or in combination was essential for cell entry, further emphasizing that essential pathways such as invasion typically rely on redundant pathways to ensure survival.
Copyright © 2014 Shen et al.

PMID:

25336455

[PubMed - in process]

Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii

Cell Microbiol. 2014 Oct 20. doi: 10.1111/cmi.12383. [Epub ahead of print]

 

Daher W¹, Morlon-Guyot J, Sheiner L, Lentini G, Berry L, Tawk L, Dubremetz JF, Wengelnik K, Striepen B, Lebrun M.

 

Phosphoinositides regulate numerous cellular processes, by recruiting cytosolic effector proteins and acting as membrane signaling entities. The cellular metabolism and localization of phosphoinositides are tightly regulated by distinct lipid kinases and phosphatases. Here, we identify and characterize a unique phosphatidylinositol 3-Kinase (PI3K) in Toxoplasma gondii, a protozoan parasite belonging to the phylum Apicomplexa. Conditional depletion of this enzyme and subsequently of its product, PI(3)P, drastically alters the morphology and inheritance of the apicoplast, an endosymbiontic organelle of algal origin that is a unique feature of many Apicomplexa. We searched the T. gondii genome for PI(3)P binding proteins and identified in total six PX and FYVE-domain containing proteins including a PIKfyve lipid kinase, which phosphorylates PI(3)P into PI(3,5)P₂ . While depletion of putative PI(3)P binding proteins shows that they are not essential for parasite growth and apicoplast biology, conditional disruption of PIKfyve induces enlarged apicoplasts, as observed upon the loss of PI(3)P. A similar defect of apicoplast homeostasis was also observed by knocking-down the PIKfyve regulatory protein ArPIKfyve, suggesting that in T. gondii, PI(3)P-related function for the apicoplast might mainly be to serve as a precursor for the synthesis of PI(3,5)P₂ . Accordingly, PI3K is conserved in all apicomplexan parasites whereas PIKfyve and ArPIKfyve are absent in Cryptosporidium species which lack an apicoplast, supporting a direct role of PI(3,5)P₂ in apicoplast homeostasis. This study enriches the already diverse functions attributed to PI(3,5)P₂ in eukaryotic cells and highlights these parasite lipid kinases as potential drug targets.
This article is protected by copyright. All rights reserved.

KEYWORDS:

Apicomplexa; Apicoplast biogenesis; Delayed death phenotype; Lipid modifications; Phosphoinositides; Tet-inducible system; Toxoplasma gondii; Traffic

PMID:

25329540

[PubMed - as supplied by publisher]

Culture of mouse peritoneal macrophages with mouse serum induces lipid bodies that associate with the parasitophorous vacuole and decrease their microbicidal capacity against Toxoplasma gondii

Mem Inst Oswaldo Cruz. 2014 Sep;109(6):767-774. Epub 2014 Aug 13.

 

Mota LA¹, Roberto Neto J¹, Monteiro VG¹, Lobato CS¹, Oliveira MA¹, Cunha MD¹, D'Ávila H², Seabra SH³, Bozza PT², DaMatta RA¹.

 

Lipid bodies [lipid droplets (LBs)] are lipid-rich organelles involved in lipid metabolism, signalling and inflammation. Recent findings suggest a role for LBs in host response to infection; however, the potential functions of this organelle in Toxoplasma gondii infection and how it alters macrophage microbicidal capacity during infection are not well understood. Here, we investigated the role of host LBs in T. gondii infection in mouse peritoneal macrophages in vitro. Macrophages cultured with mouse serum (MS) had higher numbers of LBs than those cultured in foetal bovine serum and can function as a model to study the role of LBs during intracellular pathogen infection. LBs were found in association with the parasitophorous vacuole, suggesting that T. gondii may benefit from this lipid source. Moreover, increased numbers of macrophage LBs correlated with high prostaglandin E2 (PGE2) production and decreased nitric oxide (NO) synthesis. Accordingly, LB-enriched macrophages cultured with MS were less efficient at controlling T. gondii growth. Treatment of macrophages cultured with MS with indomethacin, an inhibitor of PGE2 production, increased the microbicidal capacity against T. gondii. Collectively, these results suggest that culture with MS caused a decrease in microbicidal activity of macrophages against T. gondii by increasing PGE2 while lowering NO production.

PMID:

25317704

[PubMed - as supplied by publisher]

Toxoplasmosis complications and novel therapeutic synergism combination of diclazuril plus atovaquone

Front Microbiol. 2014 Sep 15;5:484. doi: 10.3389/fmicb.2014.00484. eCollection 2014.

 

Oz HS.

Abstract

Toxoplasmosis is a major cause of foodborne disease, congenital complication, and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: combination diclazuril plus atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes.

METHODS:

Pregnant dams were treated with diclazuril and atovaquone monotherapy or combination therapy and infected i.p with Toxoplasma tachyzoites.

RESULTS:

Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p < 0.01) and to a lesser extent diclazuril (p < 0.05) protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p < 0.05) with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p < 0.001) and to a lesser degree diclazuril monotherapy protected dams from colitis (p < 0.05) and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p < 0.001) and hepatitis (p < 0.001) which were normalized with combination therapy.

CONCLUSION:

Combination diclazuril plus atovaquone was safe and with a novel therapeutic synergism protected dams and fetuses from toxoplasmosis.

KEYWORDS:

Toxoplasma; atovaquone; combination; diclazuril; gastroenteritis; obesity; synergism; toxoplasmosis

PMID:

25309522

[PubMed]

The urban risk and migration risk factors for schizophrenia: Are cats the answer?

Schizophr Res. 2014 Oct 9. pii: S0920-9964(14)00519-2. doi: 10.1016/j.schres.2014.09.027. [Epub ahead of print]

 

Torrey EF¹, Yolken RH².

 

Being born in and/or raised in an urban area is a proven risk factor for developing schizophrenia. Migrating from countries such as Jamaica or Morocco to countries such as England or the Netherlands is also a proven risk factor for developing schizophrenia. The transmission of Toxoplasma gondii oocysts to children is reviewed and proposed as a partial explanation for both of these risk factors.
Copyright © 2014. Published by Elsevier B.V.

KEYWORDS:

Oocysts; Toxoplasma gondii; Toxoplasmosis; Urban risk

PMID:

25308833

"Latent" infection with Toxoplasma gondii: Association with trait aggression and impulsivity in healthy adults

J Psychiatr Res. 2014 Sep 28. pii: S0022-3956(14)00286-6. doi: 10.1016/j.jpsychires.2014.09.019. [Epub ahead of print]

 

Cook TB¹, Brenner LA², Cloninger CR³, Langenberg P⁴, Igbide A⁵, Giegling I⁶, Hartmann AM⁶, Konte B⁶, Friedl M⁶, Brundin L⁷, Groer MW⁸, Can A⁹, Rujescu D⁶, Postolache TT¹⁰.

BACKGROUND:

Latent chronic infection with Toxoplasma gondii (T. gondii), a common neurotropic pathogen, has been previously linked with suicidal self-directed violence (SSDV). We sought to determine if latent infection with T. gondii is associated with trait aggression and impulsivity, intermediate phenotypes for suicidal behavior, in psychiatrically healthy adults.

METHODS:

Traits of aggression and impulsivity were analyzed in relationship to IgG antibody seropositivity for T. gondii and two other latent neurotropic infections, herpes simplex virus 1 (HSV1) and cytomegalovirus (CMV). One thousand community-residing adults residing in the Munich metropolitan area with no Axis I or II conditions by SCID for DSM-IV (510 men, 490 women, mean age 53.6 ± 15.8, range 20-74). Plasma samples were tested for IgG antibodies to T. gondii, HSV-1 and CMV by ELISA. Self-reported ratings of trait aggression scores (Questionnaire for Measuring Factors of Aggression [FAF]) and trait impulsivity (Sensation-Seeking Scale-V [SSS-V]) were analyzed using linear multivariate methods.

RESULTS:

T. gondii IgG seropositivity was significantly associated with higher trait reactive aggression scores among women (p < .01), but not among men. T. gondii-positivity was also associated with higher impulsive sensation-seeking (SSS-V Disinhibition) among younger men (p < .01) aged 20-59 years old (median age = 60). All associations with HSV-1 and CMV were not significant.

CONCLUSIONS:

Aggression and impulsivity, personality traits considered as endophenotypes for SSDV, are associated with latent T. gondii infection in a gender and age-specific manner, and could be further investigated as prognostic and treatment targets in T. gondii-positive individuals at risk for SSDV.
Published by Elsevier Ltd.

KEYWORDS:

Aggression; Impulsivity; Personality; Toxoplasma gondii

PMID:

25306262

[PubMed - as supplied by publisher]

Toxoplasma gondii Is Dependent on Glutamine and Alters Migratory Profile of Infected Host Bone Marrow Derived Immune Cells through SNAT2 and CXCR4 Pathways

PLoS One. 2014 Oct 9;9(10):e109803. doi: 10.1371/journal.pone.0109803. eCollection 2014.

Lee IP1, Evans AK1, Yang C1, Works MG1, Kumar V2, De Miguel Z1, Manley NC3, Sapolsky RM4.

Author information 

Abstract

The obligate intracellular parasite, Toxoplasma gondii, disseminates through its host inside infected immune cells. We hypothesize that parasite nutrient requirements lead to manipulation of migratory properties of the immune cell. We demonstrate that 1) T. gondii relies on glutamine for optimal infection, replication and viability, and 2) T. gondii-infected bone marrow-derived dendritic cells (DCs) display both "hypermotility" and "enhanced migration" to an elevated glutamine gradient in vitro. We show that glutamine uptake by the sodium-dependent neutral amino acid transporter 2 (SNAT2) is required for this enhanced migration. SNAT2 transport of glutamine is also a significant factor in the induction of migration by the small cytokine stromal cell-derived factor-1 (SDF-1) in uninfected DCs. Blocking both SNAT2 and C-X-C chemokine receptor 4 (CXCR4; the unique receptor for SDF-1) blocks hypermotility and the enhanced migration in T. gondii-infected DCs. Changes in host cell protein expression following T. gondii infection may explain the altered migratory phenotype; we observed an increase of CD80 and unchanged protein level of CXCR4 in both T. gondii-infected and lipopolysaccharide (LPS)-stimulated DCs. However, unlike activated DCs, SNAT2 expression in the cytosol of infected cells was also unchanged. Thus, our results suggest an important role of glutamine transport via SNAT2 in immune cell migration and a possible interaction between SNAT2 and CXCR4, by which T. gondii manipulates host cell motility. 

PMID:

 

25299045

 

[PubMed - in process] 

Aquatic polymers can drive pathogen transmission in coastal ecosystems

Proc Biol Sci. 2014 Nov 22;281(1795). pii: 20141287. doi: 10.1098/rspb.2014.1287.

Shapiro K1, Krusor C2, Mazzillo FF3, Conrad PA4, Largier JL5, Mazet JA6, Silver MW3.

Author information 

Abstract

Gelatinous polymers including extracellular polymeric substances (EPSs) are fundamental to biophysical processes in aquatic habitats, including mediating aggregation processes and functioning as the matrix of biofilms. Yet insight into the impact of these sticky molecules on the environmental transmission of pathogens in the ocean is limited. We used the zoonotic parasite Toxoplasma gondii as a model to evaluate polymer-mediated mechanisms that promote transmission of terrestrially derived pathogens to marine fauna and humans. We show that transparent exopolymer particles, a particulate form of EPS, enhance T. gondii association with marine aggregates, material consumed by organisms otherwise unable to access micrometre-sized particles. Adhesion to EPS biofilms on macroalgae also captures T. gondii from the water, enabling uptake of pathogens by invertebrates that feed on kelp surfaces. We demonstrate the acquisition, concentration and retention of T. gondii by kelp-grazing snails, which can transmit T. gondii to threatened California sea otters. Results highlight novel mechanisms whereby aquatic polymers facilitate incorporation of pathogens into food webs via association with particle aggregates and biofilms. Identifying the critical role of invisible polymers in transmission of pathogens in the ocean represents a fundamental advance in understanding and mitigating the health impacts of coastal habitat pollution with contaminated runoff. 

KEYWORDS: 

Toxoplasma gondii; extracellular polymeric substances; marine transmission; sea otter; transparent exopolymer particles; zoonotic pathogen

PMID:

 

25297861

 

[PubMed - in process] 

Canonical histone H2Ba and H2A.X dimerize in an opposite genomic localization to H2A.Z/H2B.Z dimers in Toxoplasma gondii

Mol Biochem Parasitol. 2014 Oct 3. pii: S0166-6851(14)00139-X. doi: 10.1016/j.molbiopara.2014.09.009. [Epub ahead of print]

 

Bogado SS¹, Dalmasso C¹, Ganuza A², Kim K³, Sullivan Jr WJ⁴, Angel SO¹, Vanagas L⁵.

 

Histone H2Ba of Toxoplasma gondii was expressed as recombinant protein (rH2Ba) and used to generate antibody in mouse that is highly specific. Antibody recognizing rH2Ba detects a single band in tachyzoite lysate of the expected molecular weight (12kDa). By indirect immunofluorescence (IFA) in in vitro grown tachyzoites and bradyzoites, the signal was detected only in the parasite nucleus. The nucleosome composition of H2Ba was determined through co-immunoprecipitation assays. H2Ba was detected in the same immunocomplex as H2A.X, but not with H2A.Z. Through chromatin immunoprecipitation (ChIP) assays and qPCR, it was observed that H2Ba is preferentially located at promoters of inactive genes and silent regions, accompanying H2A.X and opposed to H2A.Z/H2B.Z dimers.
Copyright © 2014. Published by Elsevier B.V.

KEYWORDS:

ChIP; Toxoplasma; canonical histones; chromatin; epigenetics; nucleosome

PMID:

25286383

[PubMed - as supplied by publisher]

Structural and functional divergence of the aldolase fold in Toxoplasma gondii

J Mol Biol. 2014 Oct 2. pii: S0022-2836(14)00518-X. doi: 10.1016/j.jmb.2014.09.019. [Epub ahead of print

 

Tonkin ML¹, Halavaty AS², Ramaswamy R¹, Ruan J², Igarashi M³, Ngô HM⁴, Boulanger MJ⁵.

 

Parasites of the phylum Apicomplexa are highly successful pathogens of humans and animals world-wide. As obligate intracellular parasites, they have significant energy requirements for invasion and gliding motility that are supplied by various metabolic pathways. Aldolases have emerged as key enzymes involved in these pathways, and all apicomplexans express one or both of fructose 1,6-bisphosphate (F16BP) aldolase and 2-deoxyribose 5-phosphate (dR5P) aldolase (DERA). Intriguingly, Toxoplasma gondii, a highly successful apicomplexan parasite, expresses F16BP aldolase (TgALD1), d5RP aldolase (TgDERA), and a divergent dR5P aldolase-like protein (TgDPA) exclusively in the latent bradyzoite stage. While the importance of TgALD1 in glycolysis is well established and TgDERA is also likely to be involved in parasite metabolism, the detailed function of TgDPA remains elusive. To gain mechanistic insight into the function of different T. gondii aldolases, we first determined the crystal structures of TgALD1 and TgDPA. Structural analysis revealed that both aldolases adopt a TIM barrel fold accessorized with divergent secondary structure elements. Structural comparison of TgALD1 and TgDPA with members of their respective enzyme families revealed that while the active site residues are conserved in TgALD1, key catalytic residues are absent in TgDPA. Consistent with this observation, biochemical assays showed that while TgALD1 was active on F16BP, TgDPA was inactive on dR5P. Intriguingly, both aldolases are competent to bind polymerized actin in vitro. Altogether, structural and biochemical analyses of T. gondii aldolase and aldolase-like proteins reveal diverse functionalization of the classic TIM barrel aldolase fold.
Copyright © 2014. Published by Elsevier Ltd.

KEYWORDS:

Apicomplexa; F16BP aldolase; X-ray crystallography; dR5P aldolase; pseudoaldolase

PMID:

25284756

[PubMed - as supplied by publisher]

Triazole-based compound as the candidate to develop a novel medicines to treat toxoplasmosis

Antimicrob Agents Chemother. 2014 Oct 6. pii: AAC.03832-14. [Epub ahead of print]

 

Dzitko K¹, Paneth A², Plech T³, Pawełczyk J⁴, Węglińska L³, Paneth P⁵.

 

This letter reports anti-Toxoplasma gondii activity of 3-(thiophen-2-yl)-1,2,4-triazole-5-thione. The compound displayed significant and reproducible anti-parasitic effects at non-toxic concentrations for the host cells, with experimentally determined IC₅₀ value at least thirty time better than the one of known chemotherapeutic sulfadiazine. Purine nucleoside phosphorylase was defined as probable target for anti-Toxoplasma activity of tested compound. These results provide the foundation for the future work to develop a new class of medicines to better treat toxoplasmosis.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.

PMID:

25288090

[PubMed - as supplied by publisher]

 

Hammondia hammondi harbors functional orthologs of the host-modulating effectors GRA15 and ROP16 but is distinguished from Toxoplasma gondii by a unique transcriptional profile

Eukaryot Cell. 2014 Oct 3. pii: EC.00215-14. [Epub ahead of print]

 

Walzer KA¹, Wier GM¹, Dam RA¹, Srinivasan AR¹, Borges AL¹, English ED¹, Herrmann DC², Schares G², Dubey JP³, Boyle JP⁴.

 

Toxoplasma gondii and its nearest extant relative, Hammondia hammondi, are phenotypically distinct despite their remarkable similarity in gene content, synteny and functionality. To begin to identify genetic differences that might drive distinct infection phenotypes of T. gondii and H. hammondi, in the present study we 1) determined whether two known host-interacting proteins, dense granule protein 15 (GRA15) and rhoptry protein 16 (ROP16), were functionally conserved in H. hammondi, and 2) performed the first comparative transcriptional analysis of H. hammondi and T. gondii sporulated oocysts. We found that GRA15 and ROP16 from H. hammondi (HhGRA15; HhROP16) modulate the host NF-κB and STAT6 pathways, respectively, when expressed heterologously in T. gondii. We also found the transcriptomes of H. hammondi and T. gondii to be highly distinct. Consistent with the spontaneous conversion of H. hammondi tachyzoites into bradyzoites both in vitro and in vivo, H. hammondi high-abundance transcripts are enriched for genes that are of greater abundance in T. gondii bradyzoites. We also identified genes that are of high transcript abundance in H. hammondi, but are poorly expressed in multiple T. gondii life stages, suggesting that these genes are uniquely expressed in H. hammondi. Taken together these data confirm the functional conservation of known T. gondii virulence effectors in H. hammondi, and point to transcriptional differences as a potential source of the phenotypic differences between these species.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.

PMID:

25280815

[PubMed - as supplied by publisher]

Ribosomal protein P2 localizes to the parasite zoite-surface and is a target for invasion inhibitory antibodies in Toxoplasma gondii and Plasmodium falciparum

Parasitol Int. 2014 Sep 30. pii: S1383-5769(14)00132-9. doi: 10.1016/j.parint.2014.08.006. [Epub ahead of print

 

Sudarsan R¹, Chopra RK², Khan MA², Sharma S².

In the malarial parasite Plasmodium falciparum, the conserved ribosomal stalk protein P2 (PfP2) exhibits extra-ribosomal stage-specific oligomerization and trafficking to the host red cell membrane. Antibodies directed against PfP2 arrested cell division. We sought to examine whether P2 from a closely related Apicomplexan parasite, Toxoplasma gondii, exhibits similar properties in terms of its oligomeric status as well as such unique host-cell localization. Circular dichroism spectroscopy of recombinant P2 from T. gondii (TgP2) showed a structure similar to that of PfP2, but unlike PfP2, which forms SDS- and DTT-resistant oligomers, TgP2 exhibited only a weak SDS-resistant dimerization. Also, unlike PfP2 localization to the infected erythrocyte surface, TgP2 did not localize to the host membrane in T. gondii infected human foreskin fibroblast cells. However, P2 protein was detected on the free tachyzoite surface, corroborated by localization of epitope-tagged P2 transfected in T. gondii. The presence of P2 on the surface of P. falciparum merozoites was also observed, and specific antibodies raised against the P2 protein blocked both T. gondii and P. falciparum zoite invasion of the host cells. Thus, although certain moonlighting functions of the acidic ribosomal protein P2 are different amongst P. falciparum and T. gondii, the P2 protein localizes to the invasive zoite form, and appears to constitute a potential target for host cell invasion inhibition in both the Apicomplexan infections.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

Host invasion; Moonlighting; Non-classical secretion; Plasmodium; Ribosomal protein; Toxoplasma

PMID:

25280460

[PubMed - as supplied by publisher]

Association between latent toxoplasmosis and major depression, generalised anxiety disorder and panic disorder in human adults

Folia Parasitol (Praha). 2014 Aug;61(4):285-92.

Gale SD, Brown BL, Berrett A, Erickson LD, Hedges DW.

Abstract

Latent infection with the apicomplexan Toxoplasma gondii (Nicolle et Manceaux, 1908) has been associated with schizophrenia, bipolar disorder and self-harm behaviour. However, the potential relationship between T. gondii immunoglobulin G antibody (IgG) seropositivity and generalised-anxiety disorder (GAD) and panic disorder (PD) has not been investigated. The associations between serum reactivity to T. gondii and major depressive disorder (MDD), GAD and PD were evaluated in a total sample of 1 846 adult participants between the ages of 20 and 39 years from the United States Center for Disease Control's National Health and Nutrition Examination Survey (NHANES). Approximately 16% of the overall sample was seropositive for T. gondii and 7% of the sample met criteria for MDD, 2% for GAD and 2% for PD. There were no significant associations between T. gondii IgG seroprevalence and MDD (OR = 0.484, 95% CI = 0.186-1.258), GAD (OR = 0.737, 95% CI = 0.218-2.490) or PD (OR = 0.683, 95% CI = 0.206-2.270) controlling for sex, ethnicity, poverty-to-income ratio and educational attainment. However, limited evidence suggested a possible association between absolute antibody titres for T. gondii and GAD and PD but not MDD. Toxoplasma gondii seroprevalence was not associated with MDD, GAD or PD within the context of the limitations of this study, although there may be an association of T. gondii serointensity with and GAD and PD, which requires further study.

PMID:

 

25185399

 

[PubMed - indexed for MEDLINE]