Association between Toxoplasma gondii seropositivity and memory function in nondemented older adults

Neurobiol Aging. 2017 Feb 3;53:76-82. doi: 10.1016/j.neurobiolaging.2017.01.018. [Epub ahead of print]

Wyman CP¹, Gale SD², Hedges-Muncy A¹, Erickson LD³, Wilson E⁴, Hedges DW⁵.

Toxoplasma gondii (T. gondii) seropositivity may be associated with decreased memory in older adults. To further investigate the association between T. gondii seropositivity and memory in nondemented older adults, we obtained serum samples from 114 nondemented older adults evaluated by the Alzheimer's Disease and Research Center at Washington University in St. Louis, Missouri, USA. We determined T. gondii seropositivity and anti-T. gondii IgG antibody titer and examined associations with memory function while controlling for socioeconomic status, education level, age, and apolipoprotein E4 status. There were few associations between T. gondii seropositivity or anti-T. gondii IgG antibodies and memory, although there was some support suggesting an interaction between anti-T. gondii and sex. In the seropositive-only sample, there was an inverse relationship between anti-T. gondii titer and performance on the selective reminding test. Overall, we found little evidence of an association between impaired memory function and T. gondii seropositivity and anti-T. gondii IgG antibodies in this sample of nondemented older adults.

Copyright © 2017 Elsevier Inc. All rights reserved.

KEYWORDS:

Aging; Memory; Neurocognitive function; Toxoplasma gondii; Toxoplasmosis

PMID:

28235681

DOI:

10.1016/j.neurobiolaging.2017.01.018

T cell Immunoregulation in Active Ocular Toxoplasmosis

Immunol Lett. 2017 Feb 15. pii: S0165-2478(16)30233-4. doi: 10.1016/j.imlet.2017.02.009. [Epub ahead of print]

Cordeiro CA¹, Vieira EL², Castro VM³, Dutra WO⁴, Costa RA⁵, Orefice JL⁵, Campos WR⁶, Orefice F⁵, Young LH⁷, Teixeira AL⁸.

Toxoplasma gondii infection is an important cause of infectious ocular disease. The physiopathology of retinochoroidal lesions associated with this infection is not completely understood. The present study was undertaken to investigate cytokine production by T cells from individuals with active toxoplasmic retinochoroiditis (TR) comparing with controls. Eighteen patients with active TR and 15 healthy controls (6 controls IgG⁺ to Toxoplasma and 9 negative controls) were included in the study. Peripheral blood mononuclear cells were incubated in the presence or absence of T. gondii antigen (STAg), and stained against CD4, CD8, TNF, IL-10 and IFN-γ. Baseline expression of cytokines was higher in TR/IgG⁺ patients in comparison with controls. Cytokine expression was not increased by STAg in vitro stimulation in controls. After stimulation, TR/IgG⁺ patients' lymphocytes increased cytokine as compared to cultures from both controls. While T cells were the main source of IL-10, but also IFN-γ and TNF, other lymphocyte populations were relevant source of inflammatory cytokines. Interestingly, it was observed a negative correlation between ocular lesion size and IL-10 expression by CD4⁺ lymphocytes. This study showed that T cells are the main lymphocyte populations expressing IL-10 in patients with TR. Moreover, expression of IL-10 plays a protective role in active TR.

Copyright © 2017. Published by Elsevier B.V.

KEYWORDS:

Cytokines; T lymphocytes; Toxoplasmosis; Uveitis

PMID:

28214536

DOI:

10.1016/j.imlet.2017.02.009

Impact of ApoE genotypes variations on Toxoplasma patients with dementia

J Clin Neurosci. 2017 Feb 10. pii: S0967-5868(16)31076-1. doi: 10.1016/j.jocn.2017.01.009. [Epub ahead of print]

Yahya RS1, Awad SI2, El-Baz HA3, Saudy N4, Abdelsalam OA5, Al-Din MS5.

Author information

Abstract

BACKGROUND: 

Toxoplasma deprives host neuron cells from cholesterol and leads to its ability to potentiate dementia. ApoE intermediates neuronal transmission of cholesterol, which is a key constituent for axonal development, redesigning occasions that are important for education and synaptic arrangement, development of memory and repair of neuron. The aim of this work is to investigate the effect of ApoE genotypes on dementia associated with neurodegeneration in latent Toxoplasma gondii in elderly population.

METHODS: 

This study comprised: 133 patients with dementia (78 were positive for toxoplasma IgG and 55 were negative) and 95 subjects as control group without dementia (30 were positive for toxoplasma IgG and 65 were negative). All of them were subjected to a cognitive assessment, T. gondii seropositivity (ELISA) and determination of ApoE allelic forms (PCR).

RESULTS: 

The ApoE genotype distribution shows that the most predominant genotype is ApoE3/3 and the most widely recognized allele is E3. Both patients and control were further divided into Toxoplasma IgG positive group (n=108) and Toxoplasma IgG negative group (n=120). ApoE4 non carrier, ApoE 2/3 and ApoE 3/3 alleles have highly significant differences (P 0.001) between dementia and non-dementia patients in Toxoplasma infected patients in comparison to non-infected ones.

CONCLUSION: 

Toxoplasma positive patients have more risk to develop dementia regardless ApoE4 carriage.

Copyright © 2017 Elsevier Ltd. All rights reserved.

KEYWORDS: 

ApoE; Dementia; Neurocognitive dysfunctions; Toxoplasma

PMID:

 

28209315

 

DOI:

 

10.1016/j.jocn.2017.01.009

Direct measurement of cortical force generation and polarization in a living parasite

Mol Biol Cell. 2017 Feb 16. pii: mbc.E16-07-0518. doi: 10.1091/mbc.E16-07-0518. [Epub ahead of print]

Stadler RV1, White LA1, Hu K2, Helmke BP1, Guilford WH3.

Author information

Abstract

Apicomplexa is a large phylum of intracellular parasites that are notable for the diseases they cause, including toxoplasmosis, malaria and cryptosporidiosis. A conserved motile system is critical to their lifecycles as it drives directional gliding motility between cells, as well as invasion of and egress from host cells. However, our understanding of this system is limited by a lack of measurements of the forces driving parasite motion. We used a laser trap to measure the function of the motility apparatus of living Toxoplasma gondii by adhering a microsphere to the surface of an immobilized parasite. Motion of the microsphere reflected underlying forces exerted by the motile apparatus. We found that force generated at the parasite surface begins with no preferential directionality, but becomes directed toward the rear of the cell after a period of time. The transition from non-directional to directional force generation occurs on spatial intervals consistent with the lateral periodicity of structures associated with the membrane pellicle, and is influenced by the kinetics of actin filament polymerization and cytoplasmic calcium. A lysine methyltransferase regulates both the magnitude and polarization of the force. Our work provides a novel means to dissect the motile mechanisms of these pathogens.

© 2017 by The American Society for Cell Biology.

PMID:

 

28209732

 

DOI:

 

10.1091/mbc.E16-07-0518

Mitochondrial behaviour throughout the lytic cycle of Toxoplasma gondii

Sci Rep. 2017 Feb 16;7:42746. doi: 10.1038/srep42746.

Ovciarikova J¹, Lemgruber L¹, Stilger KL², Sullivan WJ^2,3, Sheiner L¹.

Mitochondria distribution in cells controls cellular physiology in health and disease. Here we describe the mitochondrial morphology and positioning found in the different stages of the lytic cycle of the eukaryotic single-cell parasite Toxoplasma gondii. The lytic cycle, driven by the tachyzoite life stage, is responsible for acute toxoplasmosis. It is known that whilst inside a host cell the tachyzoite maintains its single mitochondrion at its periphery. We found that upon parasite transition from the host cell to the extracellular matrix, mitochondrion morphology radically changes, resulting in a reduction in peripheral proximity. This change is reversible upon return to the host, indicating that an active mechanism maintains the peripheral positioning found in the intracellular stages. Comparison between the two states by electron microscopy identified regions of coupling between the mitochondrion outer membrane and the parasite pellicle, whose features suggest the presence of membrane contact sites, and whose abundance changes during the transition between intra- and extra-cellular states. These novel observations pave the way for future research to identify molecular mechanisms involved in mitochondrial distribution in Toxoplasma and the consequences of these mitochondrion changes on parasite physiology.

PMID:

28202940

DOI:

10.1038/srep42746

[PubMed - in process]

Cationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites

Nat Commun. 2017 Feb 16;8:14455. doi: 10.1038/ncomms14455.

Rajendran E¹, Hapuarachchi SV¹, Miller CM², Fairweather SJ¹, Cai Y³, Smith NC⁴, Cockburn IA³, Bröer S¹, Kirk K¹, van Dooren GG¹.

Apicomplexans are obligate intracellular parasites that scavenge essential nutrients from their hosts via transporter proteins on their plasma membrane. The identities of the transporters that mediate amino acid uptake into apicomplexans are unknown. Here we demonstrate that members of an apicomplexan-specific protein family-the Novel Putative Transporters (NPTs)-play key roles in the uptake of cationic amino acids. We show that an NPT from Toxoplasma gondii (TgNPT1) is a selective arginine transporter that is essential for parasite survival and virulence. We also demonstrate that a homologue of TgNPT1 from the malaria parasite Plasmodium berghei (PbNPT1), shown previously to be essential for the sexual gametocyte stage of the parasite, is a cationic amino acid transporter. This reveals a role for cationic amino acid scavenging in gametocyte biology. Our study demonstrates a critical role for amino acid transporters in the survival, virulence and life cycle progression of these parasites.

PMID:

28205520

DOI:

10.1038/ncomms14455

Congenital Toxoplasmosis in France and the United States: One Parasite, Two Diverging Approaches

PLoS Negl Trop Dis. 2017 Feb 16;11(2):e0005222. doi: 10.1371/journal.pntd.0005222. eCollection 2017.

Peyron F¹, Mc Leod R^2,3,4, Ajzenberg D^5,6, Contopoulos-Ioannidis D⁷, Kieffer F⁸, Mandelbrot L^9,10, Sibley LD¹¹, Pelloux H^12,13, Villena I^14,15, Wallon M^1,16, Montoya JG^17,18.

Author information

• ¹Hospices Civils de Lyon, Institut de Parasitologie et mycologie médicale, Hôpital de la Croix Rousse, Lyon, France.
• ²Department of Ophthalmology and Visual Science, Department of Pediatrics (Infectious Diseases), The University of Chicago, Chicago, Illinois, United States of America.
• ³Toxoplasmosis Center, Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, United States of America.
• ⁴Global Health Center, CHeSS, The University of Chicago, Chicago, Illinois, United States of America.
• ⁵Centre National de Référence (CNR) Toxoplasmose / Toxoplasma Biological Resource Center (BRC), Centre Hospitalier-Universitaire Dupuytren, Limoges, France.
• ⁶INSERM UMR 1094, Neuroépidémiologie Tropicale, Laboratoire de Parasitologie-Mycologie, Faculté de Médecine, Université de Limoges, Limoges, France.
• ⁷Department of Pediatrics, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, California, United States of America.
• ⁸Neonatal Intensive Care Unit, Armand Trousseau Hospital-Assistance Publique-Hopitaux de Paris, Paris, France.
• ⁹Hopital Louis Mourier, Assistance Publique-Hopitaux de Paris, Colombes, France.
• ¹⁰Centre de Recherche en Epidémiologie et Sante des Populations, INSERM U1018, Le Kremlin-Bicêtre, France, Université Paris Diderot-Paris 7, Paris, France.
• ¹¹Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
• ¹²Parasitologie-Mycologie Pole Biologie, CHU A. Michallon, Grenoble, France.
• ¹³UMR 5163 CNRS/Université Grenoble Alpes, Grenoble, France.
• ¹⁴Laboratoire de Parasitologie-Mycologie, Centre National de Référence de la Toxoplasmose, Centre de Ressources Biologiques Toxoplasma, Hôpital Maison Blanche Reims, France.
• ¹⁵EA 3800, SFR CAP-SANTE, Université Champagne-Ardenne, Reims, France.
• ¹⁶Physiologie intégrée du système d'éveil Centre de recherche en neurosciences de Lyon, INSERM U1028-CNRS UMR 5292, Lyon, France.
• ¹⁷Department of Medicine and Division of Infectious Diseases, Stanford University School of Medicine, Stanford, California, United States of America.
• ¹⁸Palo Alto Medical Foundation Toxoplasma Serology Laboratory, Palo Alto, California, United States of America.

PMID:

28207736

DOI:

10.1371/journal.pntd.0005222

[PubMed - in process]

Reexamining Chronic Toxoplasma gondii Infection: Surprising Activity for a "Dormant" Parasite

Curr Clin Microbiol Rep. 2016 Dec;3(4):175-185. doi: 10.1007/s40588-016-0045-3. Epub 2016 Oct 4.

Sinai AP1, Watts EA1, Dhara A1, Murphy RD2, Gentry MS2, Patwardhan A3.

Author information

Abstract

PURPOSE OF REVIEW: 

Despite over a third of the world's population being chronically infected with Toxoplasma gondii, little is known about this largely asymptomatic phase of infection. This stage is mediated in vivo by bradyzoites within tissue cysts. The absence of overt symptoms has been attributed to the dormancy of bradyzoites. In this review, we reexamine the conventional view of chronic toxoplasmosis in light of emerging evidence challenging both the nature of dormancy and the consequences of infection in the CNS.

RECENT FINDINGS: 

New and emerging data reveal a previously unrecognized level of physiological and replicative capacity of bradyzoites within tissue cysts. These findings have emerged in the context of a reexamination of the chronic infection in the brain that correlates with changes in neuronal architecture, neurochemistry, and behavior that suggest that the chronic infection is not without consequence.

SUMMARY: 

The emerging data driven by the development of new approaches to study the progression of chronic toxoplasma infection reveals significant physiological and replicative capacity for what has been viewed as a dormant state. The emergence of bradyzoite and tissue cyst biology from what was viewed as a physiological "black box" offers exciting new areas for investigation with direct implications on the approaches to drug development targeting this drug-refractory state. In addition, new insights from studies on the neurobiology on chronic infection reveal a complex and dynamic interplay between the parasite, brain microenvironment, and the immune response that results in the detente that promotes the life-long persistence of the parasite in the host.

KEYWORDS: 

Bradyzoite; CNS infection; Glycosylation; Tissue cyst; Toxoplasma

PMID:

 

28191447

 

DOI:

 

10.1007/s40588-016-0045-3

Toxoplasma gondii exposure and Parkinson's disease: a case-control study

BMJ Open. 2017 Feb 13;7(2):e013019. doi: 10.1136/bmjopen-2016-013019.

Alvarado-Esquivel C1, Méndez-Hernández EM2, Salas-Pacheco JM2, Ruano-Calderón LÁ3, Hernández-Tinoco J2, Arias-Carrión O4, Sánchez-Anguiano LF2, Castellanos-Juárez FX2, Sandoval-Carrillo AA2, Liesenfeld O5,6, Ramos-Nevárez A7.

Author information

Abstract

OBJECTIVES: 

To determine the association between Toxoplasma gondii infection and Parkinson's disease and to investigate whether T. gondii seropositivity is associated with the general characteristics of patients with Parkinson's disease.

DESIGN: 

Case-control study.

SETTING: 

Cases and controls were enrolled in Durango City, Mexico.

PARTICIPANTS: 

65 patients with Parkinson's disease and 195 age- and gender-matched control subjects without Parkinson's disease.

PRIMARY AND SECONDARY OUTCOME MEASURES: 

Serum samples of participants were analysed for anti-T. gondii IgG and IgM antibodies by commercially available enzyme-linked immunoassays. Prevalence of T. gondii DNA was determined in seropositive subjects using PCR. The association between clinical data and infection was examined by bivariate analysis.

RESULTS: 

Anti-T. gondii IgG antibodies were found in 6/65 cases (9.2%) and in 21/195 controls (10.8%) (OR 0.84; 95% CI 0.32 to 2.18; p=0.81). The frequency of high (>150 IU/mL) antibody levels was similar among cases and controls (p=0.34). None of the anti-T. gondii IgG positive cases and four of the anti-T. gondii IgG positive controls had anti-T. gondii IgM antibodies (p=0.54). The prevalence of T. gondii DNA was comparable in seropositive cases and controls (16.7% and 25%, respectively; p=1.0). Seroprevalence of T. gondii infection was associated with a young age onset of disease (p=0.03), high Unified Parkinson Disease Rating Scale scores (p=0.04) and depression (p=0.02). Seropositivity to T. gondii infection was lower in patients treated with pramipexole than in patients without this treatment (p=0.01). However, none of the associations remained significant after Bonferroni correction.

CONCLUSIONS: 

The results do not support an association between T. gondii infection and Parkinson's disease. However, T. gondiiinfection might have an influence on certain symptoms of Parkinson's disease. Further research to elucidate the role of T. gondiiexposure on Parkinson's disease is warranted.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

KEYWORDS: 

Parkinson’s disease; Toxoplasma gondii; case-control study; infection; seroprevalence

PMID:

 

28193849

 

DOI:

 

10.1136/bmjopen-2016-013019

Histone deacetylase inhibitor MS-275 augments expression of a subset of IFN-γ-regulated genes in Toxoplasma gondii-infected macrophages but does not improve parasite control

Exp Parasitol. 2017 Feb 9. pii: S0014-4894(17)30083-8. doi: 10.1016/j.exppara.2017.02.011. [Epub ahead of print]

Sumpf K¹, Nast R¹, Downie B², Salinas G², Lüder CG³.

Toxoplasma gondii is a ubiquitous apicomplexan parasite of mammals and birds and an important pathogen of humans. IFN-γ is the major mediator of host resistance against T. gondii but intriguingly, parasite-infected host cells including macrophages are severely impaired to respond to IFN-γ due to defective transcriptional activation of target genes. Here, we tested the possibility that the impaired responsiveness of T. gondii-infected macrophages to IFN-γ can be restored by inhibiting histone deacetylases (HDACs) using the class I-specific inhibitor MS-275. Treatment of RAW264.7 cells with MS-275 indeed increased MHC class II surface expression in infected and non-infected cells and largely abolished the inhibition of IFN-γ-regulated MHC class II expression exerted by T. gondii. Genome-wide transcriptome profiling revealed that MS-275 increased mean mRNA levels of IFN-γ-regulated genes particularly in non-infected macrophages. Transcript levels of 33% of IFN-γ secondary response genes but only those of a few primary response genes were also increased by MS-275 in T. gondii-infected cells. Importantly, the unresponsiveness of parasite-infected cells to IFN-γ was however not abolished by MS-275. Furthermore, MS-275 also up-regulated several anti-inflammatory cytokines or signaling molecules in T. gondii-infected macrophages. It additionally regulated expression of more than 2500 genes in non-infected macrophages expression of which was surprisingly counteracted by prior infection with T. gondii. FACS analysis and immunofluorescence microscopy revealed that MS-275 did not considerably diminish the number of parasite-positive cells or the intracellular replication in macrophages stimulated or not with IFN-γ. Thus, a supportive therapy using MS-275 appears inappropriate for treatment of toxoplasmosis.

Copyright © 2017 Elsevier Inc. All rights reserved.

KEYWORDS:

Histone deacetylase; Immune evasion; Interferon-gamma; MS-275; Supportive therapy; Toxoplasma gondii

PMID:

28189488

DOI:

10.1016/j.exppara.2017.02.011

[PubMed - as supplied by publisher]

Predictors of Toxoplasma gondii infection in Czech and Slovak populations: the possible role of cat-related injuries and risky sexual behavior in the parasite transmission

Epidemiol Infect. 2017 Feb 10:1-12. doi: 10.1017/S095026881700019X. [Epub ahead of print]

Flegr J¹.

The protozoan Toxoplasma gondii infects about one-third of the world's population. The consumption of raw meat, contact with cats, contact with soil, and ingestion of food or water contaminated with soil are considered to be the most important sources of infection. Still in most women who were infected during pregnancy, no definitive source of infection is found. In 2014-2016, independent sources of T. gondii infection were searched for by gathering epidemiological data from 1865 (519 infected) responders. Touching garden soil (odds ratio (OR) 3·14, 95% confidence interval (CI) 1·3-6·35), sustaining cat-related injuries (OR 2·16, 95% CI 1·25-3·74), and eating improperly washed root vegetables (OR 1·71, 95% CI 1·02-2·87), but not risky sexual behavior (OR 1·22, 95% CI 0·79-1·90), were the predictors of infection. The seroprevalence of T. gondii infection had been increasing up to ages 35-50 in men and ages 50-54 in women. Past those ages, seroprevalence of toxoplasmosis has been decreasing. This suggests that the natural decrease of anamnestic antibodies concentrations over time leads to positivity-to-negativity seroconversion in many subjects. If this is true, then the prevalence of T. gondii infection in a general population and its potential impacts on public health could be much larger than generally believed.

KEYWORDS:

Cats; STD; Toxoplasmosis; dogs; pets; risk factors; sexually transmitted diseases; zoonosis

PMID:

28183362

DOI:

10.1017/S095026881700019X

[PubMed - as supplied by publisher]

Evaluation of the immune response in BALB/c mice induced by a Novel DNA vaccine expressing GRA14 against Toxoplasma gondii

Parasite Immunol. 2017 Feb 10. doi: 10.1111/pim.12419. [Epub ahead of print]

Ahmadpour E¹, Sarvi S², Hashemi Soteh MB³, Sharif M², Rahimi MT⁴, Valadan R³, Tehrani M³, Khalilian A⁵, Montazeri M², Daryani A².

Toxoplasma gondii can cause severe and even fatal disease in human beings and animals. Effective vaccines may contribute to control toxoplasmosis. GRA14, a novel secreted dense granule protein of T. gondii, has been proposed as a vaccine candidate due to its intervacuolar transport and unique topology in the parasitophorous vacuole membrane. In this study, we constructed a DNA vaccine encoding GRA14 of T. gondii. BALB/c mice were immunized intramuscularly three times at 2 week intervals and challenged with T. gondii RH strain 5 weeks later. The immune responses were evaluated using lymphocyte proliferation assay, cytokine and antibody measurements. In addition, the survival timesand parasite load of mice challenged with the virulent T. gondii RH strain were evaluated. The results showed that the mice immunized with pcGRA14 induced both enhanced specific humoral and Th1 cellular immune responses also mice immunized with the pcGRA14 showed an increased survival time and decreased parasite load compared with control groups (P 0.05). The results indicated, for the first time, that the GRA14 is a potential DNA vaccine against toxoplasmosis. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS:

Toxoplasma gondii ; DNA vaccine; Dense granule; GRA14 gene

PMID:

28186325

DOI:

10.1111/pim.12419

TgPRELID, a Mitochondrial Protein Linked to Multidrug Resistance in the Parasite Toxoplasma gondii

mSphere. 2017 Feb 1;2(1). pii: e00229-16. doi: 10.1128/mSphere.00229-16.

Jeffers V1, Kamau ET2, Srinivasan AR2, Harper J2, Sankaran P2, Post SE2, Varberg JM1, Sullivan WJ Jr3, Boyle JP2.

Author information

Abstract

New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines. In independent studies, we sought to determine the targets of these two compounds using forward genetics, generating resistant mutants and identifying the determinants of resistance with comparative genome sequencing. Despite the dissimilarity of the two compounds, we recovered resistant mutants with nonsynonymous mutations in the same domain of the same gene, TGGT1_254250, which we found encodes a protein that localizes to the parasite mitochondrion (designated TgPRELID after the name of said domain). We found that mutants selected with one compound were cross resistant to the other compound, suggesting a common mechanism of resistance. To further support our hypothesis that TgPRELID mutations facilitate resistance to both I-BET151 and F3215-0002, CRISPR (clustered regularly interspaced short palindromic repeat)/CAS9-mediated mutation of TgPRELID directly led to increased F3215-0002 resistance. Finally, all resistance mutations clustered in the same subdomain of TgPRELID. These findings suggest that TgPRELID may encode a multidrug resistance factor or that I-BET151 and F3215-0002 have the same target(s) despite their distinct chemical structures. 

IMPORTANCEWe report the discovery of TgPRELID, a previously uncharacterized mitochondrial protein linked to multidrug resistance in the parasite Toxoplasma gondii. Drug resistance remains a major problem in the battle against parasitic infection, and understanding how TgPRELID mutations augment resistance to multiple, distinct compounds will reveal needed insights into the development of new therapies for toxoplasmosis and other related parasitic diseases.

KEYWORDS: 

PRELI domain; Toxoplasma gondii; mitochondrial protein import; multidrug resistance

PMID:

 

28168222

 

DOI:

 

10.1128/mSphere.00229-16

Modulation of host immune responses to Toxoplasma gondii by microRNAs

Parasite Immunol. 2017 Feb 7. doi: 10.1111/pim.12417. [Epub ahead of print]

Cai Y1, Shen J2.

Author information

Abstract

To survive successfully, Toxoplasma counteracts the strictly regulated host innate response to downregulate inflammation that could be deleterious for the parasite. MicroRNAs are vital regulators of both innate and adaptive immunity, controlling the maintenance and development of immune progenitors as well as the differentiation and the functions of host mature immune cells. Thus the complexity of mechanisms underlying the connection between Toxoplasma and host immunity has led to investigations of miRNAs as additional key molecular players. The knowledge acquired from these studies will be useful for aiding the discovery of new targets for diagnosis or therapeutic approaches for toxoplasmosis and insight into the interaction between host and parasite. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

PMID:

 

28170109

 

DOI:

 

10.1111/pim.12417

Functional Characterization of Rhoptry Kinome in the Virulent Toxoplasma gondii RH Strain

Front Microbiol. 2017 Jan 24;8:84. doi: 10.3389/fmicb.2017.00084. eCollection 2017.

Wang JL1, Li TT1, Elsheikha HM2, Chen K1, Zhu WN3, Yue DM4, Zhu XQ1, Huang SY1.

Author information

Abstract

Toxoplasma gondii is an obligatory intracellular apicomplexan protozoan which can infect any warm-blooded animal and causes severe diseases in immunocompromised individuals or infants infected in utero. The survival and success of this parasite require that it colonizes the host cell, avoids host immune defenses, replicates within an appropriate niche, and exits the infected host cell to spread to neighboring non-infected cells. All of these processes depend on the parasite ability to synthesis and export secreted proteins. Amongst the secreted proteins, rhoptry organelle proteins (ROPs) are essential for the parasite invasion and host cell manipulation. Even though the functions of most ROPs have been elucidated in the less virulent T. gondii (type II), the roles of ROPs in the highly virulent type I strain remain largely un-characterized. Herein, we investigated the contributions of 15 ROPs (ROP10, ROP11, ROP15, ROP20, ROP23, ROP31, ROP32, ROP33, ROP34, ROP35, ROP36, ROP40, ROP41, ROP46, and ROP47) to the infectivity of the high virulent type I T. gondii (RH strain). Using CRISPR-Cas9, these 15 ROPs genes were successfully disrupted and the effects of gene knockout on the parasite's ability to infect cells in vitro and BALB/c mice in vivo were investigated. These results showed that deletions of these ROPs did not interfere with the parasite ability to grow in cultured human foreskin fibroblast cells and did not significantly alter parasite pathogenicity for BALB/c mice. Although these ROPs did not seem to be essential for the acute infectious stage of type I T. gondii in the mouse model, they might have different functions in other intermediate hosts or play different roles in other life cycle forms of this parasite due to the different expression patterns; this warrants further investigations.

KEYWORDS: 

CRISPR-Cas9 system; Toxoplasma gondii; gene knockout; host–pathogen interaction; rhoptry proteins (ROPs); virulence factors

PMID:

 

28174572

 

DOI:

 

10.3389/fmicb.2017.00084

Breaking confinement: unconventional peptide presentation by major histocompatibility (MHC) class I allele HLA-A*02:01

J Biol Chem. 2017 Feb 8. pii: jbc.M117.776542. doi: 10.1074/jbc.M117.776542. [Epub ahead of print]

Remesh SG1, Andreatta M1, Ying G1, Kaever T1, Nielsen M2, McMurtrey C3, Hildebrand W3, Peters B1, Zajonc DM4.

Author information

Abstract

Peptide antigen-presentation by Major Histocompatibility Class (MHC) I proteins initiates CD8+ T cell mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with nine amino acids in length with both ends tucked inside the major A and F binding pocket. It has been known for a while that longer peptides can also bind by either bulging out of the groove in the middle of the peptide or by binding in a zig-zag fashion inside the groove. In a recent study, we identified an alternative binding conformation of naturally occurring peptides from Toxoplasma gondii bound by HLA-A*02:01. These peptides were extended at the C-terminus (PΩ) and contained charged amino acids not more than 3 residues after the anchor amino acid at PΩ, which enabled them to open the F pocket and expose their C-terminal extension into the solvent. Here, we show that the mechanism of F pocket opening is dictated by the charge of the first charged amino acid found within the extension. While positively charged amino acid result in the Tyr84 swing, amino acids that are negatively charged induce a not previously described Lys146 lift. Further, we demonstrate that the peptides with alternative binding modes have properties that fit very poorly to the conventional MHC class I pathway, and suggest they are presented via alternative means, potentially including cross-presentation via the MHC class II pathway.

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

KEYWORDS: 

T-cell receptor (TCR); Toxoplasma gondii; antigen presentation; major histocompatibility complex (MHC); natural killer cells (NK cells); peptide interaction; protein crystallization; protein structure

PMID:

 

28179428

 

DOI:

 

10.1074/jbc.M117.776542

Drugs in development for toxoplasmosis: advances, challenges, and current status

Drug Des Devel Ther. 2017 Jan 25;11:273-293. doi: 10.2147/DDDT.S60973. eCollection 2017.

Alday PH1, Doggett JS2.

Author information

Abstract

Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

KEYWORDS: 

Apicomplexa; Toxoplasma gondii; experimental medicine; mechanism of action; preclinical medicine; therapeutics

PMID:

 

28182168

 

DOI:

 

10.2147/DDDT.S60973