Int J Parasitol. 2013 Oct 31. pii: S0020-7519(13)00254-3. doi: 10.1016/j.ijpara.2013.09.006. [Epub ahead of print]

Tightly regulated migratory subversion of immune cells promotes the dissemination of Toxoplasma gondii

Weidner JM, Barragan A.

Source

Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Abstract

While the spread of Toxoplasma gondii within the infected human or animal host is associated with pathology, the pathways of dissemination have remained enigmatic. From the time point of entry into the gut, to the quiescent chronic infection in the central nervous system, Toxoplasma is detected and surveyed by immune cells that populate the tissues, e.g. dendritic cells. Paradoxically, this protective migratory function of leukocytes appears to be targeted by Toxoplasma to mediate its dissemination in the organism. Recent findings show that tightly regulated events take place shortly after host cell invasion that promote the migratory activation of infected dendritic cells. Here, we review the emerging knowledge on how this obligate intracellular protozoan orchestrates the subversion of leukocytes to achieve systemic dissemination and reach peripheral organs where pathology manifests.
Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS:

Cell motility, Chemotaxis, Dendritic cell, Host-pathogen, Immune privileged organ, Intracellular pathogen, Migration, Protozoa

PMID:

24184911

[PubMed - as supplied by publisher]

J Nerv Ment Dis. 2013 Nov;201(11):948-52. doi: 10.1097/NMD.0000000000000037.

Toxoplasma gondii Infection and Suicide Attempts: A Case-Control Study in Psychiatric Outpatients

Alvarado-Esquivel C, Sánchez-Anguiano LF, Arnaud-Gil CA, López-Longoria JC, Molina-Espinoza LF, Estrada-Martínez S, Liesenfeld O, Hernández-Tinoco J,Sifuentes-Álvarez A, Salas-Martínez C.

Source

*Faculty of Medicine, and †Institute for Scientific Research, Juárez University of Durango State, Avenida Universidad, Durango, Mexico; ‡Hospital of Mental Health "Dr. Miguel Vallebueno," Durango City, Secretary of Health, Avenida Fidel Velázquez, Durango, Mexico; and §Institute for Microbiology and Hygiene, Campus Benjamin Franklin, Charité Medical School, Berlin, Germany.

Abstract

The association of Toxoplasma gondii infection with suicide attempts has been scarcely evaluated. Two hundred eighty-three psychiatric outpatients (156 patients with history of suicide attempt and 127 control patients without history of suicide attempt) were examined with enzyme-linked immunoassays for Toxoplasma immunoglobulin G (IgG) and IgM antibodies. Seroprevalences of Toxoplasma IgG and IgM in the cases and the controls were similar: 7 (4.5%) and 3 (1.9%) vs. 10 (7.9%) and 3 (2.4%) (p = 0.23 and p = 0.55), respectively. In contrast, the Toxoplasma IgG levels higher than 150 IU/ml were more frequently observed in the cases than in the controls (100% vs. 50%, respectively; p = 0.04). The seroprevalence of Toxoplasma infection increased with age and with the number of suicide attempts. Toxoplasma seropositivity was associated with reflex impairment, national trips, and snake meat consumption. Our results suggest that although seroprevalence of Toxoplasma infection is not associated with suicide attempts, a high anti-Toxoplasma antibody level is, therefore warranting further research.

PMID:

 

24177481

 

[PubMed - in process]

Parasitol Int. 2013 Oct 28. pii: S1383-5769(13)00172-4. doi: 10.1016/j.parint.2013.10.012. [Epub ahead of print]

Characterization of ROP18 alleles in human toxoplasmosis

Sánchez V, de-la-Torre A, Marín JE.

Source

Grupo de Estudio en Parasitología Molecular (GEPAMOL), Centro de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Universidad del Quindio, Armenia (Q), Colombia.

Abstract

It is not known the role of the virulent gene ROP18 polymorphisms in human toxoplasmosis. A total of 320 clinical samples were analyzed. In samples positive for ROP18 gene, we determined by an allele specific PCR, if patients got the upstream insertion positive ROP18 sequence Toxoplasma strain (mouse avirulent strain) or the upstream insertion negative ROP18 sequence Toxoplasma strain (mouse virulent strain). We designed an ELISA assay for antibodies against ROP18 derived peptides from the three major clonal lineages of Toxoplasma. 20 clinical samples were of quality for ROP18 allele analysis. In patients with ocular toxoplasmosis, a higher inflammatory reaction on eye was associated to a PCR negative result for the upstream region of ROP18. 23.3%, 33% and 16.6% of serums from individuals with ocular toxoplasmosis were positive for type I, type II and type III ROP18 derived peptides, respectively but this assay was affected by cross reaction. The absence of Toxoplasma ROP18 promoter insertion sequence in ocular toxoplasmosis was correlated with severe ocular inflammatory response. Determination of antibodies against ROP18 protein was not useful for serotyping in human toxoplasmosis.

© 2013.

KEYWORDS:

ROP18 protein, Toxoplasma, congenital toxoplasmosis, ocular toxoplasmosis, virulence

PMID:

 

24177250

 

[PubMed - as supplied by publisher]

Vaccine. 2013 Oct 28. pii: S0264-410X(13)01379-0. doi: 10.1016/j.vaccine.2013.10.015. [Epub ahead of print]

Protective immunity induced by a recombinant BCG vaccine encoding the cyclophilin gene of Toxoplasma gondii

Yu Q, Huang X, Gong P, Zhang Q, Li J, Zhang G, Yang J, Li H, Wang N, Zhang X.

Source

Institute of Zoonosis, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun 130062, China; Jilin Provincial Animal Disease Control Center, 4510 Xi'an Road, Changchun 130062

, China.

Abstract

The investigation of Toxoplasma gondii virulence factors can elucidate the immunopathology of T. gondii infection and identify potential candidates for effective human vaccines. The adjuvant is an important component of an effective vaccine. In this study, attenuated Mycobacterium bovis was used as a live vaccine vector with both antigen and adjuvant characteristics. Following amplification of the T. gondii cyclophilin gene, the shuttle expression plasmid pMV261-TgCyP and integrative expression plasmid pMV361-TgCyP were constructed, and their expression was stimulated after transfection into BCG. Both recombinant plasmids were highly immunogenic. Greater proliferation of CD4+ and CD8+ T cells was observed in the rBCG-vaccinated groups compared to the control groups. The levels of Th1-type IFN-γ, IL-2 and IL-12 were significantly increased following immunisation with the rBCG vaccines via the i.v. or oral route, which indicated that catalytic activity against T. gondii infection was generated in the mice. rBCGpMV361-TgCyP i.v. inoculation resulted in a higher protection efficiency, as demonstrated by the increased survival time and survival rate (17%) of BALB/c mice. The present study demonstrates that a BCG vector expressing a target antigen, TgCyP, represent an alternative system for the production of effective vaccines to prevent toxoplasmosis.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

BALB/c, Cyclophilin, T. gondii, rBCG

PMID:

 

24176493

 

[PubMed - as supplied by publisher]

BMC Infect Dis. 2013 Oct 31;13(1):512. [Epub ahead of print]

Protective immunity against Toxoplasma gondii induced by DNA immunization with the gene encoding a novel vaccine candidate: calcium-dependent protein kinase 3

Zhang NZ, Huang SY, Zhou DH, Chen J, Xu Y, Tian WP, Lu J, Zhu XQ.

Abstract

BACKGROUND:

Toxoplasma gondii can infect almost all warm-blood animals including human beings. The plant-like calcium-dependent protein kinases (CDPKs) harbored by T. gondii are involved in gliding motility, cell invasion, egress and some other developmental processes, and so have been implicated as important virulence factors.

METHODS:

In the present study, we constructed a DNA vaccine expressing T. gondii CDPK3 (TgCDPK3) and evaluated its protective efficacy against T. gondii infection in Kunming mice. The gene sequence encoding TgCDPK3 was inserted into the eukaryotic expression vector pVAX I, and mice were immunized with pVAX-CDPK3 intramuscularly.

RESULTS:

The results showed that mice immunized with pVAX-CDPK3 developed a high level of specific antibodies and a strong lymphoproliferative response. The significantly increased levels of IFN-gamma, IL-2, IL-12 (p70) and IL-23 and high ratio of IgG2a to IgG1 antibody titers indicated that a Th1 type response was elicited after immunization with pVAX-CDPK3. Furthermore, the percentage of CD4+ T cells in mice vaccinated with pVAX-CDPK3 was significantly increased. After lethal challenge with the tachyzoites of the virulent T. gondii RH strain, the mice immunized with pVAX-CDPK3 prolonged the survival time from 10 days to 24 days (13.5 +/- 4.89) compared to untreated mice or those received PBS or pVAX I which died within 7 days (P < 0.05). In chronic infection model (10 cysts of the T. gondii PRU strain), the numbers of brain cysts of the mice immunized with pVAX-CDPK3 reduced significantly when compared with those in control groups (P < 0.05), and the rate of reduction could reach to about 50%.

CONCLUSIONS:

TgCDPK3 can generate protective immunity against acute and chronic T. gondii infection in Kunming mice and is a promising vaccine candidate for further development of an effective vaccine against T. gondii.

PMID:

 

24176018

 

[PubMed - as supplied by publisher]

Elife. 2013 Oct 29;2:e01298. doi: 10.7554/eLife.01298.

Reciprocal virulence and resistance polymorphism in the relationship between Toxoplasma gondii and the house mouse

Lilue J, Müller UB, Steinfeldt T, Howard JC.

Source

Institute for Genetics , University of Cologne , Cologne , Germany.

Abstract

Virulence in the ubiquitous intracellular protozoon Toxoplasma gondii for its natural intermediate host, the mouse, appears paradoxical from an evolutionary standpoint because death of the mouse before encystment interrupts the parasite life cycle. Virulent T. gondii strains secrete kinases and pseudokinases that inactivate the immunity-related GTPases (IRG proteins) responsible for mouse resistance to avirulent strains. Such considerations stimulated a search for IRG alleles unknown in laboratory mice that might confer resistance to virulent strains of T. gondii. We report that the mouse IRG system shows extraordinary polymorphic complexity in the wild. We describe an IRG haplotype from a wild-derived mouse strain that confers resistance against virulent parasites by interference with the virulent kinase complex. In such hosts virulent strains can encyst, hinting at an explanation for the evolution of virulence polymorphism in T. gondii. DOI:http://dx.doi.org/10.7554/eLife.01298.001.

KEYWORDS:

IRG proteins, Mouse, Other, Toxoplasma gondii, coevolution, virulence

PMID:

24175088

[PubMed]

Elife. 2013 Oct 29;2:e01599. doi: 10.7554/eLife.01599.

Immune to defeat

Reese ML.

Source

is at the Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , United States michael.reese@utsouthwestern.edu.

Abstract

A dramatic example of the 'arms race' between hosts and pathogens has been observed in the response of mice to the parasite that causes toxoplasmosis.

KEYWORDS:

IRG proteins, Mouse, Other, Toxoplasma gondii, coevolution, virulence

PMID:

24175089

[PubMed]

POSTDOCTORAL POSITION available

POSTDOCTORAL POSITION

Biochemistry, Microbiology, Drug development

 

Indiana University School of Medicine

 

POSTDOCTORAL POSITION available to investigate the efficacy and mechanism of experimental drugs to treat infection caused by the protozoan parasite Toxoplasma gondii. Related to the malaria parasite, Toxoplasma causes birth defects and life-threatening infection in immunocompromised AIDS or heart transplant patients. The successful candidate will continue the study of small molecules that interfere with stress responses and differentiation as a means to subvert acute and chronic parasite infection using in vivo and in vitro models (see Konrad et al., Antimicrob Agents Chemother. 2013, 57(4):1815-22). The candidate is also expected to employ state of the art genetic and biochemical approaches to determine the detailed mechanism of action for these compounds.

Position requires a Ph.D., expertise in animal (mouse) handling, biochemistry & cell biology,  and excellent communication skills (speaking and writing English). Submit CV and contact information for three references to Dr. Bill Sullivan (wjsulliv@iu.edu).

Located in downtown Indianapolis, Indiana University School of Medicine (IUSM) is the second largest medical school in the US and boasts an outstanding intellectual atmosphere and core facilities. IUSM was nationally ranked in the Top 30 Best Places to Work for Postdocs. Our lab is part of a larger intracellular parasitism group at IU that fosters innovation and collaboration. IUSM is an equal opportunity employer. Visit www.sullivanlab.com for more information.

Nat Rev Microbiol. 2013 Oct 28. doi: 10.1038/nrmicro3139. [Epub ahead of print]

Targeting lipid biosynthesis and salvage in apicomplexan parasites for improved chemotherapies

Coppens I.

Source

Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Abstract

Apicomplexa are some of the most widespread and poorly controlled pathogens in the world. The metabolism of lipids in these parasites, which include Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp., is essential for the production of infectious progeny and pathogen persistence in their mammalian hosts. Metabolic maps of apicomplexan lipid syntheses reveal auxotrophies for many lipid species, which force these parasites to meet their high demand for lipids through networks of both synthesis and scavenging. Here, I review the unique lipid biosynthetic enzymes and lipid transporter systems of Apicomplexa, focusing on isoprenoids, sphingolipids and cholesterol, and highlight promising chemotherapeutic targets in the lipid synthetic and salvage pathways.

PMID:

24162026

[PubMed - as supplied by publisher]

Comparative proteomic analysis of different Toxoplasma gondii genotypes

Electrophoresis. 2013 Oct 24. doi: 10.1002/elps.201300044. [Epub ahead of print]

Comparative proteomic analysis of different Toxoplasma gondii genotypes by two-dimensional fluorescence difference gel electrophoresis combined with mass spectrometry

Zhou DH, Zhao FR, Nisbet AJ, Xu MJ, Song HQ, Lin RQ, Huang SY, Zhu XQ.

Source

State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, 730046, China.

Abstract

Toxoplasma gondii is a protozoan parasite infecting almost all warm-blooded animals and humans. There are three infective stages of T. gondii: the tachyzoites, the bradyzoites and the oocysts. The tachyzoite is a rapidly multiplying stage and the main pathogenic factor. In North America and Europe, T. gondii is consisted of four major clonal lineages (namely Types I, II, III and Type 12). In this study, we explored the proteomic profiles of different genotypes (Type I-RH strain, Type II-PRU strain, Type II-TgQHO strain and ToxoDB 9-TgC7 strain) of T. gondii tachyzoites by using two-dimensional fluorescence difference gel electrophoresis (2D DIGE) combined with MALDI-TOF MS. Totally, 110 differentially abundant protein spots were selected. Of these, 98 spots corresponding to 56 proteins from T. gondii were successfully identified. These included surface antigen (SAG1), heat shock protein 70 (Hsp70), disulfide isomerase, coronin, heat shock protein 60 (Hsp60), pyruvate kinase, receptor for activated C kinase 1 and peroxiredoxin. Gene ontology (GO) enrichment analysis revealed that most of the differentially abundant proteins were involved in biological regulation, metabolic process, response to stress, binding, antioxidant activity and transporter activity. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway maps of T. gondii, some identified proteins were involved in the glycolytic/gluconeogenesis pathway. The present study identified differentially abundant proteins among different genotypes of T. gondii and these findings have implications for the better understanding of the phenotypic differences among the examined T. gondii genotypes which in turn may contribute to the better control of toxoplasmosis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

KEYWORDS:

2D DIGE, Mass spectrometry, Proteome, Tachyzoites, Toxoplasma gondii

PMID:

24166805

[PubMed - as supplied by publisher]

PLoS One. 2013 Oct 11;8(10):e77620. doi: 10.1371/journal.pone.0077620.

The Role of Clathrin in Post-Golgi Trafficking in Toxoplasma gondii

Pieperhoff MS, Schmitt M, Ferguson DJ, Meissner M.

Source

Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

Abstract

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle.

PMID:

 

24147036

 

[PubMed - in process] 

PLoS One. 2013 Oct 16;8(10):e77327. doi: 10.1371/journal.pone.0077327.

Mast cells modulate acute toxoplasmosis in murine models

Huang B, Huang S, Chen Y, Zheng H, Shen J, Lun ZR, Wang Y, Kasper LH, Lu F.

Source

Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China ; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China.

Abstract

The role of mast cells (MCs) in Toxoplasma gondii infection is poorly known. Kunming outbred mice were infected intraperitoneally with RH strain T. gondii, either treated with compound 48/80 (C48/80, MC activator) or disodium cromoglycate (DSCG, MC inhibitor). Compared with infected controls, infected mice treated with C48/80 exhibited significantly increased inflammation in the liver (P < 0.01), spleen (P < 0.05), and mesentery (P < 0.05) tissues, higher parasite burden in the peritoneal lavage fluids (P < 0.01), and increased levels of mRNA transcripts of T. gondii tachyzoite surface antigen 1 (SAG1) gene in the spleen and liver tissues (P < 0.01), accompanied with significantly increased Th1 cytokine (IFN-γ, IL-12p40, and TNF-α) (P < 0.01) and decreased IL-10 (P < 0.01) mRNA expressions in the liver, and increased IFN-γ (P < 0.01) and IL-12p40 (P < 0.01) but decreased TNF-α (P < 0.01) and IL-4 (P < 0.01) in the spleens of infected mice treated with C48/80 at day 9-10 p.i. Whereas mice treated with DSCG had significantly decreased tissue lesions (P < 0.01), lower parasite burden in the peritoneal lavage fluids (P < 0.01) and decreased SAG1 expressions in the spleen and liver tissues (P < 0.01), accompanied with significantly increased IFN-γ (P < 0.01) and IL-12p40 (P < 0.05) in the liver, and decreased IFN-γ (P < 0.05) and TNF-α (P < 0.01) in the spleens; IL-4 and IL-10 expressions in both the spleen and liver were significantly increased (P < 0.01) in the infected mice treated with DSCG. These findings suggest that mediators associated with the MC activation may play an important role in modulating acute inflammatory pathogenesis and parasite clearance during T. gondii infection in this strain of mice. Thus, MC activation/inhibition mechanisms are potential novel targets for the prevention and control of T. gondii infection.

PMID:

 

24146978

 

[PubMed - in process] 

PLoS Pathog. 2013 Oct;9(10):e1003665. doi: 10.1371/journal.ppat.1003665. Epub 2013 Oct 17.

Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin

Li ZH, Ramakrishnan S, Striepen B, Moreno SN.

Source

Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America.

Abstract

Intracellular pathogens have complex metabolic interactions with their host cells to ensure a steady supply of energy and anabolic building blocks for rapid growth. Here we use the obligate intracellular parasite Toxoplasma gondii to probe this interaction for isoprenoids, abundant lipidic compounds essential to many cellular processes including signaling, trafficking, energy metabolism, and protein translation. Synthesis of precursors for isoprenoids in Apicomplexa occurs in the apicoplast and is essential. To synthesize longer isoprenoids from these precursors, T. gondii expresses a bifunctional farnesyl diphosphate/geranylgeranyl diphosphate synthase (TgFPPS). In this work we construct and characterize T. gondii null mutants for this enzyme. Surprisingly, these mutants have only a mild growth phenotype and an isoprenoid composition similar to wild type parasites. However, when extracellular, the loss of the enzyme becomes phenotypically apparent. This strongly suggests that intracellular parasite salvage FPP and/or geranylgeranyl diphosphate (GGPP) from the host. We test this hypothesis using inhibitors of host cell isoprenoid synthesis. Mammals use the mevalonate pathway, which is susceptible to statins. We document strong synergy between statin treatment and pharmacological or genetic interference with the parasite isoprenoid pathway. Mice can be cured with atorvastatin (Lipitor) from a lethal infection with the TgFPPs mutant. We propose a double-hit strategy combining inhibitors of host and parasite pathways as a novel therapeutic approach against Apicomplexan parasites.

PMID:

 

24146616

 

[PubMed - in process] 

Parasitology. 2013 Oct 18:1-10. [Epub ahead of print]

Species or local environment, what determines the infection of rodents by Toxoplasma gondii?

Gotteland C, Chaval Y, Villena I, Galan M, Geers R, Aubert D, Poulle ML, Charbonnel N, Gilot-Fromont E.

Source

Université de Reims Champagne-Ardenne, Laboratoire de Parasitologie-Mycologie, EA 3800, UFR de Médecine, SFR Cap Santé FED 4231, 51 rue Cognacq-Jay, F-51096 Reims, France.

Abstract

SUMMARY Toxoplasmosis is largely present in rural areas but its spatial distribution in this environment remains poorly known. In particular, it is unclear if areas of high density of cats, the only hosts excreting Toxoplasma gondii, constitute foci of high prevalence. To improve our understanding of the spatial distribution of T. gondii in rural areas, we performed a serological survey in rodents from two villages in France. We trapped 710 rodents including commensal rats and meadow or forest voles and mice. The presence of T. gondii was examined using PCR, mice inoculation and modified agglutination test for antibodies (MAT). We conducted multivariate and discriminant analyses to identify biological, ecological or spatial variables that could explain T. gondii serology in rodents. We then used a logistic regression to assess the relative influence of each explanatory variable. Overall seroprevalence was 4·1%. Commensal-rats were more infected (12·5%) than non-commensal species (3·7%). However, the major determinant of the risk of infection was the distance to the nearest farm (OR = 0·75 for 100 m), which explained the risk in all species or non-commensal species only. We contrast the role of species characteristics and that of the local environment, and discuss the risk of environmental contamination for humans.

PMID:

24135380

[PubMed - as supplied by publisher]

Ocul Immunol Inflamm. 2013 Oct 16. [Epub ahead of print]

Epidemiology, Pathophysiology, and the Future of Ocular Toxoplasmosis

Kijlstra A, Petersen E.

Source

Livestock Research, Wageningen University and Research Centre, Lelystad, The Netherlands; and University Eye Clinic Maastricht, Maastricht , The Netherlands, Maastricht , The Netherlands and.

Abstract

Abstract Despite large advances in the field of ocular toxoplasmosis, large gaps still exist in our knowledge concerning the epidemiology and pathophysiology of this potentially blinding infectious disease. Although ocular toxoplasmosis is considered to have a high health burden, still little is known about its exact prevalence and how it affects the quality of life. The epidemiology of toxoplasmosis depends on local habits throughout the globe, and changes are likely in view of increased meat consumption in developing countries and demands for higher animal welfare in the Western world. Water is increasingly seen as an important risk factor and more studies are needed to quantitate and control the role of water exposure (drinking, swimming). Tools are now becoming available to study both the human host as well as parasite genetic factors in the development of ocular toxoplasmosis. Further research on the role of Toxoplasma strains as well as basic studies on parasite virulence is needed to explain why Toxoplasma associated eye disease is so severe in some countries, such as Brazil. Although genetic analysis of the parasite represents the gold standard, further developments in serotyping using peptide arrays may offer practical solutions to study the role of parasite strains in the pathogenesis of Toxoplasma retinochoroiditis. More research is needed concerning the pathways whereby the parasite can infect the retina. Once in the retina further tissue damage may be due to parasite virulence factors or could be caused by an aberrant host immune response. Local intraocular immune responses are nowadays used for diagnostic procedures. Future developments may include the use of Raman technology or the direct visualization of a Toxoplasma cyst by optical coherence tomography (OCT). With the availability of ocular fluid specimens obtained for diagnostic purposes and the development of advanced proteomic techniques, a biomarker fingerprint that is unique for an eye with toxoplasmosis may become available. It is hoped that such a biomarker analysis may also be able to distinguish between acquired versus congenital disease. Recently developed mouse models of congenital ocular toxoplasmosis are extremely promising with regard to disease pathogenesis, diagnosis, and treatment.

PMID:

24131274

[PubMed - as supplied by publisher]

PLoS Pathog. 2013 Oct;9(10):e1003706. Epub 2013 Oct 10.

CXCR3-Dependent CD4+ T Cells Are Required to Activate Inflammatory Monocytes for Defense against Intestinal Infection

Cohen SB, Maurer KJ, Egan CE, Oghumu S, Satoskar AR, Denkers EY.

Source

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.

Abstract

Chemokines and their receptors play a critical role in orchestrating immunity to microbial pathogens, including the orally acquired Th1-inducing protozoan parasite Toxoplasma gondii. Chemokine receptor CXCR3 is associated with Th1 responses, and here we use bicistronic CXCR3-eGFP knock-in reporter mice to demonstrate upregulation of this chemokine receptor on CD4⁺ and CD8⁺ T lymphocytes during Toxoplasma infection. We show a critical role for CXCR3 in resistance to the parasite in the intestinal mucosa. Absence of the receptor in Cxcr3^-/- mice resulted in selective loss of ability to control T. gondii specifically in the lamina propria compartment. CD4⁺ T cells were impaired both in their recruitment to the intestinal lamina propria and in their ability to secrete IFN-γ upon stimulation. Local recruitment of CD11b⁺Ly6C/G⁺ inflammatory monocytes, recently reported to be major anti-Toxoplasma effectors in the intestine, was not impacted by loss of CXCR3. However, inflammatory monocyte activation status, as measured by dual production of TNF-α and IL-12, was severely impaired in Cxcr3^-/- mice. Strikingly, adoptive transfer of wild-type but not Ifnγ^-/- CD4⁺ T lymphocytes into Cxcr3^-/- animals prior to infection corrected the defect in inflammatory macrophage activation, simultaneously reversing the susceptibility phenotype of the knockout animals. Our results establish a central role for CXCR3 in coordinating innate and adaptive immunity, ensuring generation of Th1 effectors and their trafficking to the frontline of infection to program microbial killing by inflammatory monocytes.

PMID:

24130498

[PubMed - as supplied by publisher]

J Biol Chem. 2013 Oct 15. [Epub ahead of print]

Structure of the Toxoplasma gondii ROP18 kinase domain reveals a second ligand binding pocket required for acute virulence

Lim D, Gold DA, Julien L, Rosowski EE, Niedelman W, Yaffe MB, Saeij JP.

Source

Massachusetts Institute of Technology, United States.

Abstract

At least a third of the human population is infected with the intracellular parasite Toxoplasma gondii, which contributes significantly to the disease burden in immunocompromised and neutropenic hosts and causes serious congenital complications when vertically transmitted to the fetus. Genetic analyses have identified the Toxoplasma ROP18 Ser/Thr protein kinase as a major factor mediating acute virulence in mice. ROP18 is secreted into the host cell during the invasion process, and its catalytic activity is required for the acute virulence phenotype. However, its precise molecular function and regulation are not fully understood. We have determined the crystal structure of the ROP18 kinase domain, which is inconsistent with a previously proposed auto-inhibitory mechanism of regulation. Furthermore, a sucrose molecule bound to our structure identifies an additional ligand-binding pocket outside of the active site cleft. Mutational analysis confirms an important role for this pocket in virulence.

KEYWORDS:

Crystal structure, Protein kinases, Protein phosphorylation, Protozoan, Signal transduction, Toxoplasma gondii, rhoptry protein

PMID:

24129568

[PubMed - as supplied by publisher]

Int J Parasitol. 2013 Oct 11. pii: S0020-7519(13)00244-0. doi: 10.1016/j.ijpara.2013.08.005. [Epub ahead of print]

GCN2-like eIF2α kinase manages the amino acid starvation response in Toxoplasma gondii

Konrad C, Wek RC, Sullivan WJ Jr.

Source

Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Abstract

The apicomplexan protozoan Toxoplasma gondii is a significant human and veterinary pathogen. As an obligate intracellular parasite, Toxoplasma depends on nutrients provided by the host cell and needs to adapt to limitations in available resources. In mammalian cells, translational regulation via GCN2 phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) is a key mechanism for adapting to nutrient stress. Toxoplasma encodes two GCN2-like protein kinases, TgIF2K-C and TgIF2K-D. We previously showed that TgIF2K-D phosphorylates T. gondii eIF2α (TgIF2α) upon egress from the host cell, which enables the parasite to overcome exposure to the extracellular environment. However, the function of TgIF2K-C remained unresolved. To determine the functions of TgIF2K-C in the parasite, we cloned the cDNA encoding TgIF2K-C and generated knockout parasites of this TgIF2α kinase to study its function during the lytic cycle. The TgIF2K-C knockout did not exhibit a fitness defect compared with parental parasites. However, upon infection of human fibroblasts that were subsequently cultured in glutamine-free medium, the intracellular TgIF2K-C knockout parasites were impeded for induced phosphorylation of TgIF2α and showed a 50% reduction in the number of plaques formed compared with parental parasites. Furthermore, we found that this growth defect in glutamine-free media was phenocopied in parasites expressing only a non-phosphorylatable TgIF2α (TgIF2α-S71A), but not in a TgIF2K-D knockout. These studies suggest that Toxoplasma GCN2-like kinases TgIF2K-C and TgIF2K-D evolved to have distinct roles in adapting to changes in the parasite's environment.
Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS:

Apicomplexa, Glutamine, Parasite, Stress, Translational control, eIF2 kinase

PMID:

24126185

[PubMed - as supplied by publisher]

J Infect. 2013 Oct 9. pii: S0163-4453(13)00290-9. doi: 10.1016/j.jinf.2013.09.023. [Epub ahead of print]

It is not only the cat that did it: How to prevent and treat congenital toxoplasmosis

Robert-Gangneux F.

Source

Laboratory of Parasitology, Centre Hospitalier Universitaire de Rennes, France; INSERM U1085/IRSET (Institut de Recherche en Santé Environnement Travail), Université Rennes 1, France. Electronic address: florence.robert-gangneux@univ-rennes1.fr.

Abstract

The apicomplexan parasite Toxoplasma gondii was discovered a little over one hundred years ago and was soon recognized as a pathogen responsible for congenital infection. But detailed understanding of its epidemiology emerged only after 1970 with the discovery of its life cycle. In the last ten years, high resolution molecular tools have allowed the characterization of various strain types with different virulence patterns, and current studies are exploring the distribution of these different genotypes. In parallel, sophisticated diagnostic tools have been developed and awareness of disease burden has led some European countries with high prevalence rates to implement screening of pregnant women. In this article, the screening options and therapies used to prevent congenital toxoplasmosis are dissected in the light of recent data from cohort studies and other epidemiological data.
Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

KEYWORDS:

Congenital toxoplasmosis, Epidemiology, Pregnancy, Prevention, Treatment

PMID:

24119928

[PubMed - as supplied by publisher]

Bipolar Disord. 2013 Sep 18. doi: 10.1111/bdi.12123. [Epub ahead of print]

Antibodies to Toxoplasma gondii in individuals with mania

Dickerson F, Stallings C, Origoni A, Vaughan C, Katsafanas E, Khushalani S, Yolken R.

Source

Stanley Research Program, Sheppard Pratt Health System, Baltimore, MD, USA.

Abstract

OBJECTIVES:

Increased rates of infection with Toxoplasma gondii have been found in individuals with schizophrenia as compared to control groups but this issue has not been studied in mania.

METHODS:

We measured immunoglobulin G (IgG) and IgM class antibodies to T. gondii in 57 individuals with mania who were assessed at up to three time-points. We also measured these antibodies in 743 individuals in other psychiatric groups and in 314 non-psychiatric controls. T. gondii antibody levels were compared among groups by multivariate analyses. IgG class and IgM class antibodies to cytomegalovirus were also measured in the same samples. T. gondii antibody levels were also compared over time in the mania group.

RESULTS:

The mania group had a significantly elevated level of IgM antibodies to T. gondii as compared to the control individuals without a psychiatric diagnosis [odds ratio (OR) = 2.33, p < 0.04 at hospital admission; and OR = 2.32, p < 0.02 at study entry during the hospital stay]. Elevated IgM class antibodies to T. gondii were not found in individuals with the other psychiatric diagnoses. We also did not find an increased level of IgG class antibodies to T. gondii or IgG or IgM class antibodies to CMV in the individuals with mania. Within the mania group, there was a significant difference between the prevalences of increased levels of T. gondii IgM at the baseline and the follow-up time-point (t = 2.97, p < 0.003).

CONCLUSIONS:

Infection with T. gondii may confer risk for mania.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

KEYWORDS:

Toxoplasma gondii , bipolar disorder, infection, mania, parasite

PMID:

24102676

[PubMed - as supplied by publisher]