Amino Acids. 2010 Jul 27. [Epub ahead of print]
Direct evidence of O-GlcNAcylation in the apicomplexan Toxoplasma gondii: a biochemical and bioinformatic study
Perez-Cervera Y, Harichaux G, Schmidt J, Debierre-Grockiego F, Dehennaut V, Bieker U, Meurice E, Lefebvre T, T Schwarz R.
Unit of Structural and Functional Glycobiology, CNRS-UMR 8576, IFR 147, Université de Lille 1, Cité Scientifique, 59655, Villeneuve d'Ascq, France.
Abstract
Toxoplasma gondii and Plasmodium falciparum are apicomplexan parasites responsible for serious diseases in humans. Many studies have focused on the post-translational modifications (PTMs) found in the two protists including phosphorylation, acetylation or SUMOylation but only a few of these are concerned with the nuclear and cytosolic-specific glycosylation O-GlcNAcylation. O-GlcNAcylation is a highly dynamic PTM-regulated by the ON and OFF enzymes: O-GlcNAc transferase and O-GlcNAcase-that can compete with phosphorylation but its function remains unclear. In this work, we directly prove the O-GlcNAcylation in T. gondii using antibodies specifically directed against the modification and we strongly suggest its occurrence in P. falciparum. We found that the inducible 70 kDa-Heat Shock Protein is O-GlcNAcylated, or associated with an O-GlcNAc-partner, in T. gondii. Using anti-OGT antibodies we were able to detect the expression of the glycosyltransferase in T. gondii cultured both in human foreskin fibroblast and in Vero cells and report its putative sequence. For the first time the presence of O-GlcNAcylation is unequivocally shown in T. gondii and suspected in P. falciparum. Since the O-GlcNAcylation is implicated in many biological fundamental processes this study opens a new research track in the knowledge of apicomplexans' life cycle and pathogenic potential.
PMID: 20661758 [PubMed - as supplied by publisher]
Wednesday, July 28, 2010
HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3
PLoS One. 2010 Jul 22;5(7):e11733.
HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3
Van Grol J, Subauste C, Andrade RM, Fujinaga K, Nelson J, Subauste CS.
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Abstract
Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, beta-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1(+) patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection.
PMID: 20661303 [PubMed - in process]
HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3
Van Grol J, Subauste C, Andrade RM, Fujinaga K, Nelson J, Subauste CS.
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Abstract
Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, beta-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1(+) patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection.
PMID: 20661303 [PubMed - in process]
Loop-Mediated Isothermal Amplification (LAMP) Method in Blood Samples
J Clin Microbiol. 2010 Jul 21. [Epub ahead of print]
Specific, Sensitive and Rapid Detection of Active Toxoplasmosis in Patients by Loop-Mediated Isothermal Amplification (LAMP) Method in Blood Samples
Lau YL, Meganathan P, Sonaimuthu P, Thiruvengadam G, Nissapatorn V, Chen Y.
Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; School of Science, Monash University Sunway Campus, Bandar Sunway, 46150 Selangor, Malaysia; Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800 Penang, Malaysia.
Abstract
Loop-mediated isothermal amplification (LAMP), a rapid nucleic acid amplification method was developed for the clinical detection of toxoplasmosis. Three LAMP assays were developed based on SAG1, SAG2 and B1 genes of Toxoplasma gondii. The sensitivity and specificity of the LAMP assays were evaluated in comparison with conventional nested PCR. The LAMP assays were highly sensitive with a detection limit of 0.1 tachyzoites and no cross-reactivity was observed with DNA of other parasites. Blood was collected from 105 individuals to test the LAMP assays: 40 patients with active toxoplasmosis, 40 negative controls and 25 patients with other parasitic infections. SAG2-LAMP had a greater sensitivity (87.5%) compared to SAG1-LAMP (80%), B1-LAMP (80%) and nested PCR (62.5%). All the LAMP assays and nested PCR were 100% specific. This is the first report which applies the LAMP method to diagnose toxoplasmosis from human blood samples. Due to its simplicity, sensitivity, and specificity, LAMP is suggested as an appropriate diagnostic method for routine diagnosis of active toxoplasmosis in humans.
PMID: 20660217 [PubMed - as supplied by publisher]
Specific, Sensitive and Rapid Detection of Active Toxoplasmosis in Patients by Loop-Mediated Isothermal Amplification (LAMP) Method in Blood Samples
Lau YL, Meganathan P, Sonaimuthu P, Thiruvengadam G, Nissapatorn V, Chen Y.
Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; School of Science, Monash University Sunway Campus, Bandar Sunway, 46150 Selangor, Malaysia; Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800 Penang, Malaysia.
Abstract
Loop-mediated isothermal amplification (LAMP), a rapid nucleic acid amplification method was developed for the clinical detection of toxoplasmosis. Three LAMP assays were developed based on SAG1, SAG2 and B1 genes of Toxoplasma gondii. The sensitivity and specificity of the LAMP assays were evaluated in comparison with conventional nested PCR. The LAMP assays were highly sensitive with a detection limit of 0.1 tachyzoites and no cross-reactivity was observed with DNA of other parasites. Blood was collected from 105 individuals to test the LAMP assays: 40 patients with active toxoplasmosis, 40 negative controls and 25 patients with other parasitic infections. SAG2-LAMP had a greater sensitivity (87.5%) compared to SAG1-LAMP (80%), B1-LAMP (80%) and nested PCR (62.5%). All the LAMP assays and nested PCR were 100% specific. This is the first report which applies the LAMP method to diagnose toxoplasmosis from human blood samples. Due to its simplicity, sensitivity, and specificity, LAMP is suggested as an appropriate diagnostic method for routine diagnosis of active toxoplasmosis in humans.
PMID: 20660217 [PubMed - as supplied by publisher]
Cyclophilin 18 regulates the proliferation and migration of murine macrophages and spleen cells
Clin Vaccine Immunol. 2010 Jul 21. [Epub ahead of print]
Toxoplasma gondii cyclophilin 18 regulates the proliferation and migration of murine macrophages and spleen cells
Ibrahim HM, Xuan X, Nishikawa Y.
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Zoology Department, Faculty of Science, Minufiya University, Shibin El Kom, Egypt.
Abstract
Toxoplasma gondii is an intracellular parasite showing a unique capacity to infect a variety of cell types in warm-blooded animals. It can invade and survive well inside immune cells, such as macrophages, that disseminate the parasite around the body because of their migratory properties. The aim of the present study was to evaluate the role of T. gondii cyclophilin 18 (TgCyp18) on the proliferation, and migration of macrophages and spleen cells (mainly T lymphocytes) in order to understand the effects of TgCyp18 on the dynamics of the infection. The high dose of TgCyp18 enhanced the proliferation of macrophages and spleen cells in a cysteine-cysteine chemokine receptor 5 (CCR5)-independent way. In contrast, TgCyp18 controlled the migration of macrophages and spleen cells in dose and CCR5-dependent manners. Our data suggest that TgCyp18 recruits cells and enhances the growth of host cells at the site of infection for maintenance of the interaction between the parasite and host.
PMID: 20660134 [PubMed - as supplied by publisher]
Toxoplasma gondii cyclophilin 18 regulates the proliferation and migration of murine macrophages and spleen cells
Ibrahim HM, Xuan X, Nishikawa Y.
National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan; Zoology Department, Faculty of Science, Minufiya University, Shibin El Kom, Egypt.
Abstract
Toxoplasma gondii is an intracellular parasite showing a unique capacity to infect a variety of cell types in warm-blooded animals. It can invade and survive well inside immune cells, such as macrophages, that disseminate the parasite around the body because of their migratory properties. The aim of the present study was to evaluate the role of T. gondii cyclophilin 18 (TgCyp18) on the proliferation, and migration of macrophages and spleen cells (mainly T lymphocytes) in order to understand the effects of TgCyp18 on the dynamics of the infection. The high dose of TgCyp18 enhanced the proliferation of macrophages and spleen cells in a cysteine-cysteine chemokine receptor 5 (CCR5)-independent way. In contrast, TgCyp18 controlled the migration of macrophages and spleen cells in dose and CCR5-dependent manners. Our data suggest that TgCyp18 recruits cells and enhances the growth of host cells at the site of infection for maintenance of the interaction between the parasite and host.
PMID: 20660134 [PubMed - as supplied by publisher]
RNG1 is a late marker of the apical polar ring in Toxoplasma gondii
Cytoskeleton (Hoboken). 2010 Jul 23. [Epub ahead of print]
RNG1 is a late marker of the apical polar ring in Toxoplasma gondii
Tran JQ, de Leon JC, Li C, Huynh MH, Beatty W, Morrissette NS.
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine CA 92697.
Abstract
The asexually proliferating stages of apicomplexan parasites cause acute symptoms of diseases such as malaria, cryptosporidiosis and toxoplasmosis. These stages are characterized by the presence of two independent microtubule organizing centers (MTOCs). Centrioles are found at the poles of the intranuclear spindle. The apical polar ring (APR), a MTOC unique to apicomplexans, organizes subpellicular microtubules which impose cell shape and apical polarity on these protozoa. Here we describe the characteristics of a novel protein that localizes to the APR of Toxoplasma gondii which we have named ring-1 (RNG1). There are related RNG1 proteins in Neospora caninum and Sarcocystis neurona but no obvious homologs in Plasmodium spp., Cryptosporidium spp. or Babesia spp. RNG1 is a small, low-complexity, detergent-insoluble protein that assembles at the APR very late in the process of daughter parasite replication. We were unable to knock-out the RNG1 gene, suggesting that its gene product is essential. Tagged RNG1 lines have also allowed us to visualize the APR during growth of Toxoplasma in the microtubule-disrupting drug oryzalin. Oryzalin inhibits nuclear division and cytokinesis although Toxoplasma growth continues, and similar to earlier observations of unchecked centriole duplication in oryzalin-treated parasites, the APR continues to duplicate during aberrant parasite growth. (c) 2010 Wiley-Liss, Inc.
PMID: 20658557 [PubMed - as supplied by publisher]
RNG1 is a late marker of the apical polar ring in Toxoplasma gondii
Tran JQ, de Leon JC, Li C, Huynh MH, Beatty W, Morrissette NS.
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine CA 92697.
Abstract
The asexually proliferating stages of apicomplexan parasites cause acute symptoms of diseases such as malaria, cryptosporidiosis and toxoplasmosis. These stages are characterized by the presence of two independent microtubule organizing centers (MTOCs). Centrioles are found at the poles of the intranuclear spindle. The apical polar ring (APR), a MTOC unique to apicomplexans, organizes subpellicular microtubules which impose cell shape and apical polarity on these protozoa. Here we describe the characteristics of a novel protein that localizes to the APR of Toxoplasma gondii which we have named ring-1 (RNG1). There are related RNG1 proteins in Neospora caninum and Sarcocystis neurona but no obvious homologs in Plasmodium spp., Cryptosporidium spp. or Babesia spp. RNG1 is a small, low-complexity, detergent-insoluble protein that assembles at the APR very late in the process of daughter parasite replication. We were unable to knock-out the RNG1 gene, suggesting that its gene product is essential. Tagged RNG1 lines have also allowed us to visualize the APR during growth of Toxoplasma in the microtubule-disrupting drug oryzalin. Oryzalin inhibits nuclear division and cytokinesis although Toxoplasma growth continues, and similar to earlier observations of unchecked centriole duplication in oryzalin-treated parasites, the APR continues to duplicate during aberrant parasite growth. (c) 2010 Wiley-Liss, Inc.
PMID: 20658557 [PubMed - as supplied by publisher]
The construction and use of log-odds substitution scores for multiple sequence alignment
PLoS Comput Biol. 2010 Jul 15;6(7):e1000852.
The construction and use of log-odds substitution scores for multiple sequence alignment
Altschul SF, Wootton JC, Zaslavsky E, Yu YK.
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
Abstract
Most pairwise and multiple sequence alignment programs seek alignments with optimal scores. Central to defining such scores is selecting a set of substitution scores for aligned amino acids or nucleotides. For local pairwise alignment, substitution scores are implicitly of log-odds form. We now extend the log-odds formalism to multiple alignments, using Bayesian methods to construct "BILD" ("Bayesian Integral Log-odds") substitution scores from prior distributions describing columns of related letters. This approach has been used previously only to define scores for aligning individual sequences to sequence profiles, but it has much broader applicability. We describe how to calculate BILD scores efficiently, and illustrate their uses in Gibbs sampling optimization procedures, gapped alignment, and the construction of hidden Markov model profiles. BILD scores enable automated selection of optimal motif and domain model widths, and can inform the decision of whether to include a sequence in a multiple alignment, and the selection of insertion and deletion locations. Other applications include the classification of related sequences into subfamilies, and the definition of profile-profile alignment scores. Although a fully realized multiple alignment program must rely upon more than substitution scores, many existing multiple alignment programs can be modified to employ BILD scores. We illustrate how simple BILD score based strategies can enhance the recognition of DNA binding domains, including the Api-AP2 domain in Toxoplasma gondii and Plasmodium falciparum.
PMID: 20657661 [PubMed - in process]
The construction and use of log-odds substitution scores for multiple sequence alignment
Altschul SF, Wootton JC, Zaslavsky E, Yu YK.
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
Abstract
Most pairwise and multiple sequence alignment programs seek alignments with optimal scores. Central to defining such scores is selecting a set of substitution scores for aligned amino acids or nucleotides. For local pairwise alignment, substitution scores are implicitly of log-odds form. We now extend the log-odds formalism to multiple alignments, using Bayesian methods to construct "BILD" ("Bayesian Integral Log-odds") substitution scores from prior distributions describing columns of related letters. This approach has been used previously only to define scores for aligning individual sequences to sequence profiles, but it has much broader applicability. We describe how to calculate BILD scores efficiently, and illustrate their uses in Gibbs sampling optimization procedures, gapped alignment, and the construction of hidden Markov model profiles. BILD scores enable automated selection of optimal motif and domain model widths, and can inform the decision of whether to include a sequence in a multiple alignment, and the selection of insertion and deletion locations. Other applications include the classification of related sequences into subfamilies, and the definition of profile-profile alignment scores. Although a fully realized multiple alignment program must rely upon more than substitution scores, many existing multiple alignment programs can be modified to employ BILD scores. We illustrate how simple BILD score based strategies can enhance the recognition of DNA binding domains, including the Api-AP2 domain in Toxoplasma gondii and Plasmodium falciparum.
PMID: 20657661 [PubMed - in process]
Wednesday, July 21, 2010
Association of host mitochondria with the parasitophorous vacuole during Toxoplasma infection is not dependent on rhoptry proteins ROP2/8
Int J Parasitol. 2010 Jul 14. [Epub ahead of print]
Association of host mitochondria with the parasitophorous vacuole during Toxoplasma infection is not dependent on rhoptry proteins ROP2/8
Pernas L, Boothroyd JC.
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
Abstract
Previous work has proposed rhoptry protein 2 (ROP2) as the physical link that tethers host mitochondria to the parasitophorous vacuole membrane (PVM) surrounding the intracellular parasite, Toxoplasma gondii. A recent analysis of the ROP2 structure, however, raised questions about this model. To determine whether ROP2 is necessary, we created a parasite line that lacks the entire ROP2 locus consisting of the three closely related genes, ROP2a, ROP2b and ROP8. We show that this knockout mutant retains the ability to recruit host mitochondria in a manner that is indistinguishable from the parental strain, re-opening the question of which molecules mediate this association. Copyright © 2010. Published by Elsevier Ltd.
PMID: 20637758 [PubMed - as supplied by publisher]
Association of host mitochondria with the parasitophorous vacuole during Toxoplasma infection is not dependent on rhoptry proteins ROP2/8
Pernas L, Boothroyd JC.
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
Abstract
Previous work has proposed rhoptry protein 2 (ROP2) as the physical link that tethers host mitochondria to the parasitophorous vacuole membrane (PVM) surrounding the intracellular parasite, Toxoplasma gondii. A recent analysis of the ROP2 structure, however, raised questions about this model. To determine whether ROP2 is necessary, we created a parasite line that lacks the entire ROP2 locus consisting of the three closely related genes, ROP2a, ROP2b and ROP8. We show that this knockout mutant retains the ability to recruit host mitochondria in a manner that is indistinguishable from the parental strain, re-opening the question of which molecules mediate this association. Copyright © 2010. Published by Elsevier Ltd.
PMID: 20637758 [PubMed - as supplied by publisher]
Saturday, July 17, 2010
Predominant Interferon-gamma-Mediated Expression of CXCL9, CXCL10, and CCL5 Proteins in the Brain During Chronic Infection with Toxoplasma
J Interferon Cytokine Res. 2010 Jul 13. [Epub ahead of print]
Predominant Interferon-gamma-Mediated Expression of CXCL9, CXCL10, and CCL5 Proteins in the Brain During Chronic Infection with Toxoplasma gondii in BALB/c Mice Resistant to Development of Toxoplasmic Encephalitis
Wen X, Kudo T, Payne L, Wang X, Rodgers L, Suzuki Y.
1 Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
Abstract
We examined the role of interferon-gamma (IFN-gamma) in expression of chemokine mRNA and proteins in the brain during chronic infection with Toxoplasma gondii using BALB/c and BALB/c-background IFN-gamma knockout (IFN-gamma(-/-)) mice. BALB/c mice are genetically resistant to development of toxoplasmic encephalitis and establish a latent, chronic infection in the brain through IFN-gamma-mediated immune responses. Amounts of mRNA for CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC, CCL2/MCP-1, CCL3/MIP-1alpha, and CCL5/RANTES significantly increased in the brains of wild-type mice after infection. CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES mRNA were most abundant among these chemokines. An increase in amounts of mRNA for CXCL10/IP-10, CCL2/MCP-1, CCL3/MIP-1alpha, and CCL5/RANTES was also observed in the brains of IFN-gamma(-/-) mice after infection, although CXCL10/I-10 and CCL5/RANTES mRNA levels in infected IFN-gamma(-/-) mice were significantly lower than those of infected wild-type animals. Amounts of mRNA for CXCL9/MIG and CXCL11/I-TAC remained at the basal levels in infected IFN-gamma(-/-) mice. When amounts of the chemokine proteins were examined in the brain homogenates of uninfected and infected mice of both strains, large amounts of CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES were detected only in infected wild-type animals. These results indicate that CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES are the chemokines predominantly induced in the brains of genetically resistant BALB/c mice during chronic infection with T. gondii, and their expression is dependent on IFN-gamma.
PMID: 20626297 [PubMed - as supplied by publisher]
Predominant Interferon-gamma-Mediated Expression of CXCL9, CXCL10, and CCL5 Proteins in the Brain During Chronic Infection with Toxoplasma gondii in BALB/c Mice Resistant to Development of Toxoplasmic Encephalitis
Wen X, Kudo T, Payne L, Wang X, Rodgers L, Suzuki Y.
1 Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
Abstract
We examined the role of interferon-gamma (IFN-gamma) in expression of chemokine mRNA and proteins in the brain during chronic infection with Toxoplasma gondii using BALB/c and BALB/c-background IFN-gamma knockout (IFN-gamma(-/-)) mice. BALB/c mice are genetically resistant to development of toxoplasmic encephalitis and establish a latent, chronic infection in the brain through IFN-gamma-mediated immune responses. Amounts of mRNA for CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC, CCL2/MCP-1, CCL3/MIP-1alpha, and CCL5/RANTES significantly increased in the brains of wild-type mice after infection. CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES mRNA were most abundant among these chemokines. An increase in amounts of mRNA for CXCL10/IP-10, CCL2/MCP-1, CCL3/MIP-1alpha, and CCL5/RANTES was also observed in the brains of IFN-gamma(-/-) mice after infection, although CXCL10/I-10 and CCL5/RANTES mRNA levels in infected IFN-gamma(-/-) mice were significantly lower than those of infected wild-type animals. Amounts of mRNA for CXCL9/MIG and CXCL11/I-TAC remained at the basal levels in infected IFN-gamma(-/-) mice. When amounts of the chemokine proteins were examined in the brain homogenates of uninfected and infected mice of both strains, large amounts of CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES were detected only in infected wild-type animals. These results indicate that CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES are the chemokines predominantly induced in the brains of genetically resistant BALB/c mice during chronic infection with T. gondii, and their expression is dependent on IFN-gamma.
PMID: 20626297 [PubMed - as supplied by publisher]
Use of dense granule antigen GRA6 in Immunoglobulin G avidity test to exclude acute Toxoplasma infection during pregnancy
Clin Vaccine Immunol. 2010 Jul 14. [Epub ahead of print]
Use of dense granule antigen GRA6 in Immunoglobulin G avidity test to exclude acute Toxoplasma infection during pregnancy
Elyasi H, Babaie J, Fricker-Hidalgo H, Brenier-Pinchart MP, Zare M, Sadeghiani G, Assmar M, Pelloux H, Golkar M.
Molecular Parasitology Laboratory, Parasitology Department, Pasteur Institute of Iran, Tehran, Iran; Parasitology Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Parasitology and Mycology Laboratory, Grenoble Teaching Hospital A Michallon, BP 217, 38043 Grenoble Cedex 09, France; Laboratoire Adaptation et Pathogénie des Microorganismes, CNRS UMR 5163, Joseph Fourier University (Grenoble I), BP 170, 38042 Grenoble Cedex 09, France.
Abstract
Usefulness of a specific immunoglobulin G (IgG) avidity enzyme-linked immunosorbent assay based on recombinant GRA6 antigen was investigated for distinguishing between acute and chronic Toxoplasma infection. Two sets of sera from pregnant women with acute, chronic or no Toxoplasma infection collected in France and Iran were used. Among French subjects, 19 of 20 (95%) women experiencing seroconversion during the past 4 months before sampling displayed low avidity IgG antibodies against GRA6, while all 17 (100%) women with chronic infection had high avidity antibodies. When Euroimmun IgG avidity ELISA was used, 15 of 19 (78.9%) recently-infected women had low avidity antibodies and 20 of 22 (90.9%) women with chronic infection displayed high avidity antibodies. The results suggested better performance of GRA6 avidity than Euroimmun avidity ELISA for exclusion of a recent infection occurred less than 4 months before. Similarly, all 35 Iranian women with acute Toxoplasma infection had low avidity antibodies against GRA6, whereas all 34 women with chronic infection displayed IgG antibodies of high avidity, indicating value of GRA6 avidity testing for ruling out a recent infection. Avidity tests based on lysed whole-cell T. gondii antigen are currently used to exclude recently acquired infections; however, the use of recombinant antigen(s) might improve diagnostic performance of avidity tests and facilitate development of more standardized assays.
PMID: 20631335 [PubMed - as supplied by publisher]
Use of dense granule antigen GRA6 in Immunoglobulin G avidity test to exclude acute Toxoplasma infection during pregnancy
Elyasi H, Babaie J, Fricker-Hidalgo H, Brenier-Pinchart MP, Zare M, Sadeghiani G, Assmar M, Pelloux H, Golkar M.
Molecular Parasitology Laboratory, Parasitology Department, Pasteur Institute of Iran, Tehran, Iran; Parasitology Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Parasitology and Mycology Laboratory, Grenoble Teaching Hospital A Michallon, BP 217, 38043 Grenoble Cedex 09, France; Laboratoire Adaptation et Pathogénie des Microorganismes, CNRS UMR 5163, Joseph Fourier University (Grenoble I), BP 170, 38042 Grenoble Cedex 09, France.
Abstract
Usefulness of a specific immunoglobulin G (IgG) avidity enzyme-linked immunosorbent assay based on recombinant GRA6 antigen was investigated for distinguishing between acute and chronic Toxoplasma infection. Two sets of sera from pregnant women with acute, chronic or no Toxoplasma infection collected in France and Iran were used. Among French subjects, 19 of 20 (95%) women experiencing seroconversion during the past 4 months before sampling displayed low avidity IgG antibodies against GRA6, while all 17 (100%) women with chronic infection had high avidity antibodies. When Euroimmun IgG avidity ELISA was used, 15 of 19 (78.9%) recently-infected women had low avidity antibodies and 20 of 22 (90.9%) women with chronic infection displayed high avidity antibodies. The results suggested better performance of GRA6 avidity than Euroimmun avidity ELISA for exclusion of a recent infection occurred less than 4 months before. Similarly, all 35 Iranian women with acute Toxoplasma infection had low avidity antibodies against GRA6, whereas all 34 women with chronic infection displayed IgG antibodies of high avidity, indicating value of GRA6 avidity testing for ruling out a recent infection. Avidity tests based on lysed whole-cell T. gondii antigen are currently used to exclude recently acquired infections; however, the use of recombinant antigen(s) might improve diagnostic performance of avidity tests and facilitate development of more standardized assays.
PMID: 20631335 [PubMed - as supplied by publisher]
Thursday, July 15, 2010
Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6
J Biol Chem. 2010 Jul 12. [Epub ahead of print]
Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6
Ong YC, Reese ML, Boothroyd JC.
Stanford University, United States.
Abstract
The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be partially mediated by dysregulation of the host transcription factors STAT3 and STAT6, but the molecular mechanisms underlying this phenotype were unclear. Here, we use a Type I Toxoplasma strain deficient in ROP16 to show that ROP16 induces not only sustained activation but also an extremely rapid (within one minute) initial activation of STAT6. Using recombinant wild-type and kinase-deficient ROP16, we demonstrate in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosine residue for STAT6 activation, Tyr641. Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo.
PMID: 20624917 [PubMed - as supplied by publisher]
Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6
Ong YC, Reese ML, Boothroyd JC.
Stanford University, United States.
Abstract
The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be partially mediated by dysregulation of the host transcription factors STAT3 and STAT6, but the molecular mechanisms underlying this phenotype were unclear. Here, we use a Type I Toxoplasma strain deficient in ROP16 to show that ROP16 induces not only sustained activation but also an extremely rapid (within one minute) initial activation of STAT6. Using recombinant wild-type and kinase-deficient ROP16, we demonstrate in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosine residue for STAT6 activation, Tyr641. Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo.
PMID: 20624917 [PubMed - as supplied by publisher]
Toxoplasma gondii: The effects of infection at different stages of pregnancy on the offspring of mice
Exp Parasitol. 2010 Jul 6. [Epub ahead of print]
Toxoplasma gondii: The effects of infection at different stages of pregnancy on the offspring of mice
Wang T, Liu M, Gao XJ, Zhao ZJ, Chen XG, Lun ZR.
Center for Parasitic OrganismsState Key Laboratory of Biocontrol, School of Life Sciences, and Key Laboratory of Tropical Diseases Control (The Ministry of Education), Zhongshan Medical College, Sun Yat-Sen (Zhongshan) University, Guangzhou 510275, P.R. China.
Abstract
Congenital toxoplasmosis can cause fetal damage in humans and domestic animals. This study was focused on the effects of Toxoplasma gondii (Prugniaud strain) infection at different stages of pregnancy on the offspring of mice. Results showed that newborn mice from all infected groups were significantly lower in weight than those from the control group but significant difference was not found among these groups at day 60 after birth. The survival rate of the offspring from the group of mice infected at the earlier stage of pregnancy was significantly lower than those of infected and control groups. The positive offspring (with cysts found in their brain tissues) born from the mice infected at the earlier and intermediate stages of pregnancy showed a shorter latency and greater number of errors in the step-through passive avoidance test than those born from the mice infected at the late stage of pregnancy, the control group and the negative offspring from the infected groups. The number of cysts in the brain tissue was significantly higher in the offspring born from the groups of mice infected at the earlier and intermediate stages of pregnancy than those from the group of mice infected at the late stage of pregnancy. In addition, our results indicated that a high congenital transmission rate (90%) occurred in this NIH mouse model. In conclusion, the earlier and intermediate maternal infection of T. gondii can result in severe congenital toxoplasmosis, exhibiting conditions such as stillbirth or non-viability, and learning or memory capability damage in this mouse model. These results not only provide useful data for better understanding the effects of T. gondii infection on the offspring of mice infected at different stages of pregnancy but also for better consideration of the effect of this infection on other mammalian hosts including humans. Copyright © 2010. Published by Elsevier Inc.
PMID: 20619261 [PubMed - as supplied by publisher]
Toxoplasma gondii: The effects of infection at different stages of pregnancy on the offspring of mice
Wang T, Liu M, Gao XJ, Zhao ZJ, Chen XG, Lun ZR.
Center for Parasitic OrganismsState Key Laboratory of Biocontrol, School of Life Sciences, and Key Laboratory of Tropical Diseases Control (The Ministry of Education), Zhongshan Medical College, Sun Yat-Sen (Zhongshan) University, Guangzhou 510275, P.R. China.
Abstract
Congenital toxoplasmosis can cause fetal damage in humans and domestic animals. This study was focused on the effects of Toxoplasma gondii (Prugniaud strain) infection at different stages of pregnancy on the offspring of mice. Results showed that newborn mice from all infected groups were significantly lower in weight than those from the control group but significant difference was not found among these groups at day 60 after birth. The survival rate of the offspring from the group of mice infected at the earlier stage of pregnancy was significantly lower than those of infected and control groups. The positive offspring (with cysts found in their brain tissues) born from the mice infected at the earlier and intermediate stages of pregnancy showed a shorter latency and greater number of errors in the step-through passive avoidance test than those born from the mice infected at the late stage of pregnancy, the control group and the negative offspring from the infected groups. The number of cysts in the brain tissue was significantly higher in the offspring born from the groups of mice infected at the earlier and intermediate stages of pregnancy than those from the group of mice infected at the late stage of pregnancy. In addition, our results indicated that a high congenital transmission rate (90%) occurred in this NIH mouse model. In conclusion, the earlier and intermediate maternal infection of T. gondii can result in severe congenital toxoplasmosis, exhibiting conditions such as stillbirth or non-viability, and learning or memory capability damage in this mouse model. These results not only provide useful data for better understanding the effects of T. gondii infection on the offspring of mice infected at different stages of pregnancy but also for better consideration of the effect of this infection on other mammalian hosts including humans. Copyright © 2010. Published by Elsevier Inc.
PMID: 20619261 [PubMed - as supplied by publisher]
Saturday, July 10, 2010
Manipulation of host behaviour by Toxoplasma gondii: what is the minimum a proposed proximate mechanism should explain?
Folia Parasitol (Praha). 2010 Jun;57(2):88-94.
Manipulation of host behaviour by Toxoplasma gondii: what is the minimum a proposed proximate mechanism should explain?
Vyas A, Sapolsky R.
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore. avyas@ntu.edu.sg
Abstract
The behavioural manipulation hypothesis posits that parasites can change the behaviour of hosts to increase the reproductive fitness of the parasite. The protozoan parasite Toxoplasma gondii fits this description well. Sexual reproduction occurs in the cat intestine, from which highly stable oocysts are excreted in faeces. Grazing animals, including rodents, can then ingest these oocysts. The parasite has evolved the capacity to abolish the innate fear that rodents have of the odours of cats, and to convert that fear into an attraction. This presumably increases the likelihood of the rodent being predated, thereby completing the parasite's life cycle. The behavioural syndrome produced by T. gondii does not have any precedent in neuroscience research. This is not a case where the normal functioning of fear system have been altered. This is not even the case of the altering of fear towards predator odours, while leaving other kinds of fear intact. This is an unprecedented example of one component of the fear being eliminated (and replaced by a novel attraction), while appearing to leave other domains unchanged. An understanding of the neurobiological effects of T. gondii is beginning to emerge. One possibility is T. gondii's preferential localisation to, and effects within the amygdala; this is particularly intriguing, given the role of this brain structure in the normal fear response. Obviously, far more must be understood, and the unique behavioural effects of T. gondii put very demanding constraints on any hypothesis we formulate to explain proximate neurobiological mechanisms.
PMID: 20608470 [PubMed - in process]
Manipulation of host behaviour by Toxoplasma gondii: what is the minimum a proposed proximate mechanism should explain?
Vyas A, Sapolsky R.
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore. avyas@ntu.edu.sg
Abstract
The behavioural manipulation hypothesis posits that parasites can change the behaviour of hosts to increase the reproductive fitness of the parasite. The protozoan parasite Toxoplasma gondii fits this description well. Sexual reproduction occurs in the cat intestine, from which highly stable oocysts are excreted in faeces. Grazing animals, including rodents, can then ingest these oocysts. The parasite has evolved the capacity to abolish the innate fear that rodents have of the odours of cats, and to convert that fear into an attraction. This presumably increases the likelihood of the rodent being predated, thereby completing the parasite's life cycle. The behavioural syndrome produced by T. gondii does not have any precedent in neuroscience research. This is not a case where the normal functioning of fear system have been altered. This is not even the case of the altering of fear towards predator odours, while leaving other kinds of fear intact. This is an unprecedented example of one component of the fear being eliminated (and replaced by a novel attraction), while appearing to leave other domains unchanged. An understanding of the neurobiological effects of T. gondii is beginning to emerge. One possibility is T. gondii's preferential localisation to, and effects within the amygdala; this is particularly intriguing, given the role of this brain structure in the normal fear response. Obviously, far more must be understood, and the unique behavioural effects of T. gondii put very demanding constraints on any hypothesis we formulate to explain proximate neurobiological mechanisms.
PMID: 20608470 [PubMed - in process]
Toxoplasma gondii-altered host behaviour: clues as to mechanism of action
Folia Parasitol (Praha). 2010 Jun;57(2):95-104.
Toxoplasma gondii-altered host behaviour: clues as to mechanism of action
Webster JP, McConkey GA.
Department of Infectious Disease Epidemiology, Imperial College, Faculty of Medicine, London, W2 1PG, UK. joanne.webster@imperial.ac.uk
Abstract
A convincing body of evidence now exists, from both human and animal studies, and encompassing epidemiological to experimental, to indicate that the common protozoan Toxoplasma gondii can cause specific behavioural changes in its host. Such behavioural alterations are likely to be the product of strong selective pressures for the parasite to enhance transmission from its intermediate host reservoir, primarily rodent, to its feline definitive host, wherein sexual reproduction can occur and the parasite's life cycle completed. Here we consider what the available data to date may reveal about the potential mechanisms involved, the future research that needs to be performed, and the subsequent implications for animal and human health.
PMID: 20608471 [PubMed - in process]
Toxoplasma gondii-altered host behaviour: clues as to mechanism of action
Webster JP, McConkey GA.
Department of Infectious Disease Epidemiology, Imperial College, Faculty of Medicine, London, W2 1PG, UK. joanne.webster@imperial.ac.uk
Abstract
A convincing body of evidence now exists, from both human and animal studies, and encompassing epidemiological to experimental, to indicate that the common protozoan Toxoplasma gondii can cause specific behavioural changes in its host. Such behavioural alterations are likely to be the product of strong selective pressures for the parasite to enhance transmission from its intermediate host reservoir, primarily rodent, to its feline definitive host, wherein sexual reproduction can occur and the parasite's life cycle completed. Here we consider what the available data to date may reveal about the potential mechanisms involved, the future research that needs to be performed, and the subsequent implications for animal and human health.
PMID: 20608471 [PubMed - in process]
Toxoplasmosis as a cause for behaviour disorders--overview of evidence and mechanisms
Folia Parasitol (Praha). 2010 Jun;57(2):105-13.
Toxoplasmosis as a cause for behaviour disorders--overview of evidence and mechanisms
Fekadu A, Shibre T, Cleare AJ.
Department of Psychiatry, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia. Abe.Wassie@kcl.ac.uk
Abstract
BACKGROUND: There is growing interest in the role of microbial agents in the causation of psychiatric disorders. The neurotropic protozoan parasite Toxoplasma gondii is one of the main candidates and has been associated with various psychiatric conditions, including schizophrenia. METHODS: A narrative review of the literature from the main medical databases (Medline, PubMed, PsycINFO), Google Scholar and Google using combinations of applicable terms. RESULTS: T. gondii affects the brain in both the acute and the latent stages of infection causing apparent brain pathologies in infected rodents and both immuno-compromised and immuno-competent humans. In immuno-competent individuals, behavioural disorders are primarily related to the latent stages of the illness. Behavioural/mental disorders that include schizophrenia, mood disorders, personality changes and cognitive impairments may be related to infection with T. gondii. Evidence for a behavioural effect of T. gondii comes from observational reports in animal models and controlled behavioural analysis in humans. Indirect clues of infection also come from raised seroprevalence or serotitres of antitoxoplasma antibodies among those with mental disorders. The pathophysiologic mechanism through which T. gondii may exert its effect is not clear, but direct impact on the brain and changes in neuroimmunomodulation, neurotransmission and some gene-environment interactions are postulated. CONCLUSION: There is evidence supporting a potential role of T. gondii infection in the onset of some behavioural disorders. Confirmation of such a role would prove a significant breakthrough in the search for the aetiology, treatment and prevention of behavioural disorders, such as schizophrenia. However, the associations remain preliminary.
PMID: 20608472 [PubMed - in process]
Toxoplasmosis as a cause for behaviour disorders--overview of evidence and mechanisms
Fekadu A, Shibre T, Cleare AJ.
Department of Psychiatry, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia. Abe.Wassie@kcl.ac.uk
Abstract
BACKGROUND: There is growing interest in the role of microbial agents in the causation of psychiatric disorders. The neurotropic protozoan parasite Toxoplasma gondii is one of the main candidates and has been associated with various psychiatric conditions, including schizophrenia. METHODS: A narrative review of the literature from the main medical databases (Medline, PubMed, PsycINFO), Google Scholar and Google using combinations of applicable terms. RESULTS: T. gondii affects the brain in both the acute and the latent stages of infection causing apparent brain pathologies in infected rodents and both immuno-compromised and immuno-competent humans. In immuno-competent individuals, behavioural disorders are primarily related to the latent stages of the illness. Behavioural/mental disorders that include schizophrenia, mood disorders, personality changes and cognitive impairments may be related to infection with T. gondii. Evidence for a behavioural effect of T. gondii comes from observational reports in animal models and controlled behavioural analysis in humans. Indirect clues of infection also come from raised seroprevalence or serotitres of antitoxoplasma antibodies among those with mental disorders. The pathophysiologic mechanism through which T. gondii may exert its effect is not clear, but direct impact on the brain and changes in neuroimmunomodulation, neurotransmission and some gene-environment interactions are postulated. CONCLUSION: There is evidence supporting a potential role of T. gondii infection in the onset of some behavioural disorders. Confirmation of such a role would prove a significant breakthrough in the search for the aetiology, treatment and prevention of behavioural disorders, such as schizophrenia. However, the associations remain preliminary.
PMID: 20608472 [PubMed - in process]
The role of latent toxoplasmosis in the aetiopathogenesis of schizophrenia--the risk factor or an indication of a contact with cat?
Folia Parasitol (Praha). 2010 Jun;57(2):121-8.
The role of latent toxoplasmosis in the aetiopathogenesis of schizophrenia--the risk factor or an indication of a contact with cat?
Yuksel P, Alpay N, Babur C, Bayar R, Saribas S, Karakose AR, Aksoy C, Aslan M, Mehmetali S, Kilic S, Balcioglu I, Hamanca O, Dirican A, Kucukbasmaci O, Oner A, Torun MM, Kocazeybek B.
Department of Microbiology and Clinical Microbiology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Abstract
We assessed IgG antibody to Toxoplasma gondii in 300 inpatients with schizophrenia (SG), 150 outpatients with anxiety and depressive disorders (PCG), and 150 healthy blood donors (HCG). Seropositivity rates were 60.7% for SG, 36.7% for PCG, and 45.3% for HCG (p<0.001). The seropositivity rate for anti-Toxoplasma IgG antibodies in SG was significantly higher that in PCG (chi2 = 23.11, OR = 2.66, p = 0.001) and HCG (chi2 = 9.52, OR = 1.86, p = 0.002). Among SG, 85% of those who reported close cat contact had IgG antibodies to T. gondii. Close cat contacts were reported by 59% of SG, 6% of PCG, and 9% of HCG (p<0.001). There was a nonsignificant positive association between toxoplasmosis and schizophrenia for people with a contact with a cat (OR = 2.221, p = 0.127, CI95 = 0.796-6.192), and significant negative association between toxoplasmosis and schizophrenia for people without contact with a cat (OR = 0.532, p = 0.009, CI95 = 0.332-0.854). Close cat contact (OR = 2.679, p<0.001), 51-65-year age group (OR = 1.703, p<0.001) and education [illiterate+primary (OR = 6.146, p<0.001) and high school (OR = 1.974, p = 0.023)] were detected as independent risk factors in multivariate logistic regression. The effect of toxoplasmosis on risk of schizophrenia disappeared in the complex model analyzed with multivariate logistic regression. In conclusion, our data suggest that the toxoplasmosis has no direct effect on the risk of schizophrenia in Turkey but is just an indication of previous contacts with a cat.
PMID: 20608474 [PubMed - in process]
The role of latent toxoplasmosis in the aetiopathogenesis of schizophrenia--the risk factor or an indication of a contact with cat?
Yuksel P, Alpay N, Babur C, Bayar R, Saribas S, Karakose AR, Aksoy C, Aslan M, Mehmetali S, Kilic S, Balcioglu I, Hamanca O, Dirican A, Kucukbasmaci O, Oner A, Torun MM, Kocazeybek B.
Department of Microbiology and Clinical Microbiology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Abstract
We assessed IgG antibody to Toxoplasma gondii in 300 inpatients with schizophrenia (SG), 150 outpatients with anxiety and depressive disorders (PCG), and 150 healthy blood donors (HCG). Seropositivity rates were 60.7% for SG, 36.7% for PCG, and 45.3% for HCG (p<0.001). The seropositivity rate for anti-Toxoplasma IgG antibodies in SG was significantly higher that in PCG (chi2 = 23.11, OR = 2.66, p = 0.001) and HCG (chi2 = 9.52, OR = 1.86, p = 0.002). Among SG, 85% of those who reported close cat contact had IgG antibodies to T. gondii. Close cat contacts were reported by 59% of SG, 6% of PCG, and 9% of HCG (p<0.001). There was a nonsignificant positive association between toxoplasmosis and schizophrenia for people with a contact with a cat (OR = 2.221, p = 0.127, CI95 = 0.796-6.192), and significant negative association between toxoplasmosis and schizophrenia for people without contact with a cat (OR = 0.532, p = 0.009, CI95 = 0.332-0.854). Close cat contact (OR = 2.679, p<0.001), 51-65-year age group (OR = 1.703, p<0.001) and education [illiterate+primary (OR = 6.146, p<0.001) and high school (OR = 1.974, p = 0.023)] were detected as independent risk factors in multivariate logistic regression. The effect of toxoplasmosis on risk of schizophrenia disappeared in the complex model analyzed with multivariate logistic regression. In conclusion, our data suggest that the toxoplasmosis has no direct effect on the risk of schizophrenia in Turkey but is just an indication of previous contacts with a cat.
PMID: 20608474 [PubMed - in process]
The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients
Folia Parasitol (Praha). 2010 Jun;57(2):129-35.
The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients
Hinze-Selch D, Däubener W, Erdag S, Wilms S.
The Centre for Integrative Psychiatry, Department of Psychiatry and Psychotherapy at the Christian Albrecht University, Niemannsweg 147, D-24105 Kiel, Germany. dunjahs@hotmail.com
Abstract
Individuals serologically positive for the chronic infection with the parasite Toxoplasma gondii (TG) display certain personality traits differently from uninfected individuals. Experimental data in mice demonstrate that TG infection modulates behaviour. However, psychiatric patients with a personality disorder have not yet been investigated systematically. In our sample containing 896 psychiatric inpatients with the primary diagnoses of schizophrenia, major depression, schizoaffective or bipolar disorder and 214 psychiatrically unaffected controls (same geographic region, sampled during same time period) we analysed for effects of the additional diagnosis of a personality disorder in the patients. Psychiatrically, a patient can meet the criteria of a personality disorder additionally to any of the mentioned primary diagnoses. We applied logistic regression and cross-table statistics, separated groups by the presence/absence of a personality disorder (ICD-10) and adjusted for age between groups. We found that among all patients the additional diagnosis of a personality disorder was significantly associated with TG infection. Furthermore, only in the patients with an additional personality disorder medium titre responses (1:16-1:64) were associated with chronic course and high C-reactive protein (CRP) levels whereas high titre response (>1:64) was associated with a more acute recurrent clinical course. In the older individuals only there was a preponderance of medium titre responses (1:16-1:64) among the patients with personality disorder compared to those without and controls. We conclude that TG infection and the host's response to it make a difference for the diagnosis of a personality disorder. Our data support that TG infection can modulate human behaviour and personality traits.
PMID: 20608475 [PubMed - in process]
The diagnosis of a personality disorder increases the likelihood for seropositivity to Toxoplasma gondii in psychiatric patients
Hinze-Selch D, Däubener W, Erdag S, Wilms S.
The Centre for Integrative Psychiatry, Department of Psychiatry and Psychotherapy at the Christian Albrecht University, Niemannsweg 147, D-24105 Kiel, Germany. dunjahs@hotmail.com
Abstract
Individuals serologically positive for the chronic infection with the parasite Toxoplasma gondii (TG) display certain personality traits differently from uninfected individuals. Experimental data in mice demonstrate that TG infection modulates behaviour. However, psychiatric patients with a personality disorder have not yet been investigated systematically. In our sample containing 896 psychiatric inpatients with the primary diagnoses of schizophrenia, major depression, schizoaffective or bipolar disorder and 214 psychiatrically unaffected controls (same geographic region, sampled during same time period) we analysed for effects of the additional diagnosis of a personality disorder in the patients. Psychiatrically, a patient can meet the criteria of a personality disorder additionally to any of the mentioned primary diagnoses. We applied logistic regression and cross-table statistics, separated groups by the presence/absence of a personality disorder (ICD-10) and adjusted for age between groups. We found that among all patients the additional diagnosis of a personality disorder was significantly associated with TG infection. Furthermore, only in the patients with an additional personality disorder medium titre responses (1:16-1:64) were associated with chronic course and high C-reactive protein (CRP) levels whereas high titre response (>1:64) was associated with a more acute recurrent clinical course. In the older individuals only there was a preponderance of medium titre responses (1:16-1:64) among the patients with personality disorder compared to those without and controls. We conclude that TG infection and the host's response to it make a difference for the diagnosis of a personality disorder. Our data support that TG infection can modulate human behaviour and personality traits.
PMID: 20608475 [PubMed - in process]
Pattern of money allocation in experimental games supports the stress hypothesis of gender differences in Toxoplasma gondii-induced behavioural change
Folia Parasitol (Praha). 2010 Jun;57(2):136-42.
Pattern of money allocation in experimental games supports the stress hypothesis of gender differences in Toxoplasma gondii-induced behavioural changes
Lindová J, Kubena AA, Sturcová H, Krivohlavá R, Novotná M, Rubesová A, Havlícek J, Kodym P, Flegr J.
Department of Philosophy and History of Science, Faculty of Science, Charles University, Vinicná 7, 128 44 Prague, Czech Republic. jit.hanusova@centrum.cz
Abstract
Latent toxoplasmosis has been previously found to cause behavioural and personality changes in humans, which are specific for each gender. Here we tested the stress hypothesis of these gender differences based on the assumption that latent toxoplasmosis causes long-term subliminal stress. In line with this hypothesis, the gender difference will appear specifically in situations with interpersonal context because in contrast to the typical individualistic coping style of men, women have a tendency to express elevated prosocial behaviour under stress. Altogether 295 biology students (29/191 females and 27/104 males infected by T. gondii) played a modified version of the Dictator Game and the Trust Game. As predicted, a gender difference in the effect of latent toxoplasmosis was found for the measure of reciprocal altruism in the Trust Game (p = 0.016), but both genders appeared less generous when infected in the Dictator Game modified to minimize social connotation (p = 0.048).
PMID: 20608476 [PubMed - in process]
Pattern of money allocation in experimental games supports the stress hypothesis of gender differences in Toxoplasma gondii-induced behavioural changes
Lindová J, Kubena AA, Sturcová H, Krivohlavá R, Novotná M, Rubesová A, Havlícek J, Kodym P, Flegr J.
Department of Philosophy and History of Science, Faculty of Science, Charles University, Vinicná 7, 128 44 Prague, Czech Republic. jit.hanusova@centrum.cz
Abstract
Latent toxoplasmosis has been previously found to cause behavioural and personality changes in humans, which are specific for each gender. Here we tested the stress hypothesis of these gender differences based on the assumption that latent toxoplasmosis causes long-term subliminal stress. In line with this hypothesis, the gender difference will appear specifically in situations with interpersonal context because in contrast to the typical individualistic coping style of men, women have a tendency to express elevated prosocial behaviour under stress. Altogether 295 biology students (29/191 females and 27/104 males infected by T. gondii) played a modified version of the Dictator Game and the Trust Game. As predicted, a gender difference in the effect of latent toxoplasmosis was found for the measure of reciprocal altruism in the Trust Game (p = 0.016), but both genders appeared less generous when infected in the Dictator Game modified to minimize social connotation (p = 0.048).
PMID: 20608476 [PubMed - in process]
Toxoplasma gondii strain-dependent effects on mouse behaviour
Folia Parasitol (Praha). 2010 Jun;57(2):151-5.
Toxoplasma gondii strain-dependent effects on mouse behaviour
Kannan G, Moldovan K, Xiao JC, Yolken RH, Jones-Brando L, Pletnikov MV.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-5371, USA.
Abstract
Toxoplasma gondii reportedly manipulates rodent behaviour to increase transmission to its definitive feline host. We compared the effects of mouse infection by two Type II strains of T. gondii, Prugniaud (PRU) and ME49, on attraction to cat odour, locomotor activity, anxiety, sensorimotor gating, and spatial working and recognition memory 2 months post-infection (mpi). Attraction to cat odour was reassessed 7 mpi. At 2 mpi, mice infected with either strain exhibited significantly more attraction to cat odour than uninfected animals did, but only PRU-infected mice exhibited this behaviour 7 mpi. PRU-infected mice had significantly greater body weights and hyperactivity, while ME49-infected mice exhibited impaired spatial working memory. No differences in parasite antibody titres were seen between PRU- and ME49-infected mice. The present data suggest the effect of T. gondii infection on mouse behaviour is parasite strain-dependent.
PMID: 20608478 [PubMed - in process]
Toxoplasma gondii strain-dependent effects on mouse behaviour
Kannan G, Moldovan K, Xiao JC, Yolken RH, Jones-Brando L, Pletnikov MV.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-5371, USA.
Abstract
Toxoplasma gondii reportedly manipulates rodent behaviour to increase transmission to its definitive feline host. We compared the effects of mouse infection by two Type II strains of T. gondii, Prugniaud (PRU) and ME49, on attraction to cat odour, locomotor activity, anxiety, sensorimotor gating, and spatial working and recognition memory 2 months post-infection (mpi). Attraction to cat odour was reassessed 7 mpi. At 2 mpi, mice infected with either strain exhibited significantly more attraction to cat odour than uninfected animals did, but only PRU-infected mice exhibited this behaviour 7 mpi. PRU-infected mice had significantly greater body weights and hyperactivity, while ME49-infected mice exhibited impaired spatial working memory. No differences in parasite antibody titres were seen between PRU- and ME49-infected mice. The present data suggest the effect of T. gondii infection on mouse behaviour is parasite strain-dependent.
PMID: 20608478 [PubMed - in process]
3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication
Mol Biochem Parasitol. 2010 Jun 1. [Epub ahead of print]
3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication
Wang Y, Karnataki A, Parsons M, Weiss LM, Orlofsky A.
Department of Pathology, Albert Einstein College of Medicine, Golding 704, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Abstract
The apicomplexan Toxoplasma gondii replicates by endodyogeny, in which replicated organelles assemble into nascent daughter buds within the maternal parasite. The mechanisms governing this complex sequence are not understood. We now report that the kinase inhibitor 3-methlyadenine (3-MA) efficiently blocks T. gondii replication. The inhibition could not be attributed to the effects of 3-MA on mammalian phosphatidylinositol 3-kinase and host cell autophagy. Furthermore, we show that accumulation of host lysosomes around the parasitophorous vacuoles was unaffected. Most 3-MA-treated parasites failed to form daughter buds or replicate DNA, indicating arrest in G1 or early S-phase. Some 3-MA-treated parasites displayed abortive cell division, in which nuclear segregation to malformed daughter buds was incomplete or asymmetrical. Electron microscopy revealed the presence of residual body-like structures in many vacuoles, even in the absence of daughter buds. Most treated parasites had otherwise normal morphology and were able to resume replication upon drug removal. 3-MA-treated and control parasites were similar with respect to the extent of Golgi body division and apicoplast elongation; however, treated parasites rarely possessed replicated centrosomes or apicoplasts. These data are suggestive of a generalized blockade of T. gondii cell cycle progression at stages preceding centrosome replication, rather than arrest at a specific checkpoint. We hypothesize that 3-MA treatment triggers a cell cycle pause program that may serve to protect parasites during periods, such as subsequent to egress, when cell cycle progression might be deleterious. Elucidation of the mechanism of 3-MA inhibition may provide insight into the control of parasite growth. Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20609430 [PubMed - as supplied by publisher]
3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication
Wang Y, Karnataki A, Parsons M, Weiss LM, Orlofsky A.
Department of Pathology, Albert Einstein College of Medicine, Golding 704, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Abstract
The apicomplexan Toxoplasma gondii replicates by endodyogeny, in which replicated organelles assemble into nascent daughter buds within the maternal parasite. The mechanisms governing this complex sequence are not understood. We now report that the kinase inhibitor 3-methlyadenine (3-MA) efficiently blocks T. gondii replication. The inhibition could not be attributed to the effects of 3-MA on mammalian phosphatidylinositol 3-kinase and host cell autophagy. Furthermore, we show that accumulation of host lysosomes around the parasitophorous vacuoles was unaffected. Most 3-MA-treated parasites failed to form daughter buds or replicate DNA, indicating arrest in G1 or early S-phase. Some 3-MA-treated parasites displayed abortive cell division, in which nuclear segregation to malformed daughter buds was incomplete or asymmetrical. Electron microscopy revealed the presence of residual body-like structures in many vacuoles, even in the absence of daughter buds. Most treated parasites had otherwise normal morphology and were able to resume replication upon drug removal. 3-MA-treated and control parasites were similar with respect to the extent of Golgi body division and apicoplast elongation; however, treated parasites rarely possessed replicated centrosomes or apicoplasts. These data are suggestive of a generalized blockade of T. gondii cell cycle progression at stages preceding centrosome replication, rather than arrest at a specific checkpoint. We hypothesize that 3-MA treatment triggers a cell cycle pause program that may serve to protect parasites during periods, such as subsequent to egress, when cell cycle progression might be deleterious. Elucidation of the mechanism of 3-MA inhibition may provide insight into the control of parasite growth. Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20609430 [PubMed - as supplied by publisher]
Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis
Proc Natl Acad Sci U S A. 2010 Jul 6. [Epub ahead of print]
Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis
Osborn SL, Diehl G, Han SJ, Xue L, Kurd N, Hsieh K, Cado D, Robey EA, Winoto A.
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Abstract
Cell death is an important mechanism to limit uncontrolled T-cell expansion during immune responses. Given the role of death-receptor adapter protein Fas-associated death domain (FADD) in apoptosis, it is intriguing that T-cell receptor (TCR)-induced proliferation is blocked in FADD-defective T cells. Necroptosis is an alternate form of death that can be induced by death receptors and is linked to autophagy. It requires the death domain-containing kinase RIP1 and, in certain instances, RIP3. FADD and its apoptotic partner, Caspase-8, have also been implicated in necroptosis. To accurately assess the role of FADD in mature T-cell proliferation and death, we generated a conditional T-cell-specific FADD knockout mouse strain. The T cells of these mice develop normally, but lack FADD at the mature stage. FADD-deficient T cells respond poorly to TCR triggering, exhibit slow cell cycle entry, and fail to expand over time. We find that programmed necrosis occurs during the late stage of normal T-cell proliferation and that this process is greatly amplified in FADD-deficient T cells. Inhibition of necroptosis using an inhibitor of RIP1 kinase activity rescues the FADD knockout proliferative defect. However, TCR-induced necroptosis did not appear to require autophagy or involve RIP3. Consistent with their defective CD8 T-cell response, these mice succumb to Toxoplasma gondii infection more readily than wild-type mice. We conclude that FADD constitutes a mechanism to keep TCR-induced programmed necrotic signaling in check during early phases of T-cell clonal expansion.
PMID: 20615958 [PubMed - as supplied by publisher]
Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis
Osborn SL, Diehl G, Han SJ, Xue L, Kurd N, Hsieh K, Cado D, Robey EA, Winoto A.
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Abstract
Cell death is an important mechanism to limit uncontrolled T-cell expansion during immune responses. Given the role of death-receptor adapter protein Fas-associated death domain (FADD) in apoptosis, it is intriguing that T-cell receptor (TCR)-induced proliferation is blocked in FADD-defective T cells. Necroptosis is an alternate form of death that can be induced by death receptors and is linked to autophagy. It requires the death domain-containing kinase RIP1 and, in certain instances, RIP3. FADD and its apoptotic partner, Caspase-8, have also been implicated in necroptosis. To accurately assess the role of FADD in mature T-cell proliferation and death, we generated a conditional T-cell-specific FADD knockout mouse strain. The T cells of these mice develop normally, but lack FADD at the mature stage. FADD-deficient T cells respond poorly to TCR triggering, exhibit slow cell cycle entry, and fail to expand over time. We find that programmed necrosis occurs during the late stage of normal T-cell proliferation and that this process is greatly amplified in FADD-deficient T cells. Inhibition of necroptosis using an inhibitor of RIP1 kinase activity rescues the FADD knockout proliferative defect. However, TCR-induced necroptosis did not appear to require autophagy or involve RIP3. Consistent with their defective CD8 T-cell response, these mice succumb to Toxoplasma gondii infection more readily than wild-type mice. We conclude that FADD constitutes a mechanism to keep TCR-induced programmed necrotic signaling in check during early phases of T-cell clonal expansion.
PMID: 20615958 [PubMed - as supplied by publisher]
Thursday, July 08, 2010
The association of infectious agents and schizophrenia
World J Biol Psychiatry. 2010 Aug;11(5):739-43.
The association of infectious agents and schizophrenia
Krause D, Matz J, Weidinger E, Wagner J, Wildenauer A, Obermeier M, Riedel M, Müller N.
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany. Daniela.Krause@med.uni-muenchen.de
Abstract
OBJECTIVES: The influence of infectious agents on the pathogenesis of psychiatric disorders has been discussed for decades. Pre- and postnatal infections are risk factors for schizophrenia. This may be explained by chronic infections or an altered immune status. However most of the studies have only focused on one single pathogen and not on the impact of different infectious agents. We investigated the association between schizophrenia and various neurotophic infectious agents. METHODS: A total of 31 schizophrenic patients and 30 healthy matched individuals were included. Antibody titres of cytomegalovirus, herpes simplex virus, Epstein-Barr virus, mycoplasma, chlamydia and toxoplasma were evaluated. For statistical analysis we used Fisher's exact and Wilcoxon test. RESULTS: Significantly elevated positive antibody titres within schizophrenic patients were found only for Chlamydia trachomatis (P=0.005) and a trend to significance for herpes simplex virus (P=0.055). Combining the different agents, schizophrenics had a significantly higher rate of positive titres to infectious agents as compared to controls (P=0.04). CONCLUSIONS: The higher prevalence of antibodies within schizophrenic patients emphasizes a possible role of infectious agents in the pathogenesis of schizophrenia. Our data indicates that not one specific agent might be responsible for schizophrenic symptoms but the resulting immune response in the central nervous system.
PMID: 20602604 [PubMed - in process]
The association of infectious agents and schizophrenia
Krause D, Matz J, Weidinger E, Wagner J, Wildenauer A, Obermeier M, Riedel M, Müller N.
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University, Munich, Germany. Daniela.Krause@med.uni-muenchen.de
Abstract
OBJECTIVES: The influence of infectious agents on the pathogenesis of psychiatric disorders has been discussed for decades. Pre- and postnatal infections are risk factors for schizophrenia. This may be explained by chronic infections or an altered immune status. However most of the studies have only focused on one single pathogen and not on the impact of different infectious agents. We investigated the association between schizophrenia and various neurotophic infectious agents. METHODS: A total of 31 schizophrenic patients and 30 healthy matched individuals were included. Antibody titres of cytomegalovirus, herpes simplex virus, Epstein-Barr virus, mycoplasma, chlamydia and toxoplasma were evaluated. For statistical analysis we used Fisher's exact and Wilcoxon test. RESULTS: Significantly elevated positive antibody titres within schizophrenic patients were found only for Chlamydia trachomatis (P=0.005) and a trend to significance for herpes simplex virus (P=0.055). Combining the different agents, schizophrenics had a significantly higher rate of positive titres to infectious agents as compared to controls (P=0.04). CONCLUSIONS: The higher prevalence of antibodies within schizophrenic patients emphasizes a possible role of infectious agents in the pathogenesis of schizophrenia. Our data indicates that not one specific agent might be responsible for schizophrenic symptoms but the resulting immune response in the central nervous system.
PMID: 20602604 [PubMed - in process]
Increased pregnancy weight gain in women with latent toxoplasmosis and RhD-positivity protection against this effect
Parasitology. 2010 Jul 6:1-7. [Epub ahead of print]
Increased pregnancy weight gain in women with latent toxoplasmosis and RhD-positivity protection against this effect
Kaňková S, Sulc J, Flegr J.
Department of Parasitology, Faculty of Science, Charles University in Prague, Vinicná 7, CZ-128 44 Prague 2, Czech Republic.
Abstract
SUMMARYObjective. RhD-positive subjects are protected against toxoplasmosis-associated impairment of psychomotor performance. Here we searched for RhD-positivity-associated maternal protection against the effects of toxoplasmosis. Methods. In the present retrospective cohort study, we analysed data from 785 (139 RhD-negative) Toxoplasma-free and 194 (27 RhD-negative) Toxoplasma-infected pregnant women. We searched for effects of toxoplasmosis and Rhd-phenotype on maternal weight before pregnancy, pregnancy weight gain, fetal ultrasound data (biparietal diameter, abdominal circumference, femur length) and on birth length and weight. Results. At pregnancy week 16, the RhD-negative mothers with toxoplasmosis gained more weight than others (P<0.001). The difference of about 1600 g remained approximately constant from pregnancy week 16 until the end of pregnancy. Neither toxoplasmosis nor RhD phenotype had any effect on fetal bioparameter data or birth length and weight. Conclusion. The most parsimonious explanation for the observed data is that the RhD-positive phenotype might protect infected subjects against a broad spectrum of detrimental effects of latent toxoplasmosis, including excessive gestational weight gain.
PMID: 20602855 [PubMed - as supplied by publisher]
Increased pregnancy weight gain in women with latent toxoplasmosis and RhD-positivity protection against this effect
Kaňková S, Sulc J, Flegr J.
Department of Parasitology, Faculty of Science, Charles University in Prague, Vinicná 7, CZ-128 44 Prague 2, Czech Republic.
Abstract
SUMMARYObjective. RhD-positive subjects are protected against toxoplasmosis-associated impairment of psychomotor performance. Here we searched for RhD-positivity-associated maternal protection against the effects of toxoplasmosis. Methods. In the present retrospective cohort study, we analysed data from 785 (139 RhD-negative) Toxoplasma-free and 194 (27 RhD-negative) Toxoplasma-infected pregnant women. We searched for effects of toxoplasmosis and Rhd-phenotype on maternal weight before pregnancy, pregnancy weight gain, fetal ultrasound data (biparietal diameter, abdominal circumference, femur length) and on birth length and weight. Results. At pregnancy week 16, the RhD-negative mothers with toxoplasmosis gained more weight than others (P<0.001). The difference of about 1600 g remained approximately constant from pregnancy week 16 until the end of pregnancy. Neither toxoplasmosis nor RhD phenotype had any effect on fetal bioparameter data or birth length and weight. Conclusion. The most parsimonious explanation for the observed data is that the RhD-positive phenotype might protect infected subjects against a broad spectrum of detrimental effects of latent toxoplasmosis, including excessive gestational weight gain.
PMID: 20602855 [PubMed - as supplied by publisher]
Avirulent Uracil Auxotrophs Based on Disruption of Orotidine-5'-Monophosphate Decarboxylase elicit protective immunity to Toxoplasma gondii
Infect Immun. 2010 Jul 6. [Epub ahead of print]
Avirulent Uracil Auxotrophs Based on Disruption of Orotidine-5'-Monophosphate Decarboxylase elicit protective immunity to Toxoplasma gondii
Fox BA, Bzik DJ.
Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756 USA.
Abstract
The orotidine-5'-monophosphate decarboxylase (OMPDC) gene encoding the final enzyme of the de novo pyrimidine biosynthesis pathway was deleted using Toxoplasma gondii KU80 knockouts to develop an avirulent nonreverting pyrimidine auxotroph strain. Additionally, to functionally address the role of the pyrimidine salvage pathway the uridine phosphorylase (UP) salvage activity was knocked out and a double knockout of UP and OMPDC was also constructed. The nonreverting DeltaOMPDC, DeltaUP, and DeltaOMPDCDeltaUP knockout strains were evaluated for pyrimidine auxotrophy, for attenuation of virulence, and for their ability to elicit potent immunity to reinfection. The DeltaUP knockout strain was replication competent and virulent. In contrast, the DeltaOMPDC and DeltaOMPDCDeltaUP strains were uracil auxotrophs that rapidly lost their viability during pyrimidine starvation. Replication of the DeltaOMPDC strain, but not the DeltaOMPDCDeltaUP strain, was also partially rescued in vitro with uridine or cytidine supplementation. Compared to their hypervirulent parental type I strain, the DeltaOMPDC and DeltaOMPDCDeltaUP knockout strains exhibited extreme attenuation in murine virulence ( approximately 8 logs). Genetic complementation of the DeltaOMPDC strain using a functional OMPDC allele restored normal replication and type I parental strain virulence phenotypes. A single immunization of mice with either the live critically attenuated DeltaOMPDC or the DeltaOMPDCDeltaUP knockout strain effectively induced potent protective immunity to lethal challenge infection. The avirulent nonreverting DeltaOMPDC and DeltaOMPDCDeltaUP strains provide new tools for the dissection of host response to infection and promising candidates for safe and effective Th1 vaccine platforms that can be easily genetically engineered.
PMID: 20605980 [PubMed - as supplied by publisher]
Avirulent Uracil Auxotrophs Based on Disruption of Orotidine-5'-Monophosphate Decarboxylase elicit protective immunity to Toxoplasma gondii
Fox BA, Bzik DJ.
Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756 USA.
Abstract
The orotidine-5'-monophosphate decarboxylase (OMPDC) gene encoding the final enzyme of the de novo pyrimidine biosynthesis pathway was deleted using Toxoplasma gondii KU80 knockouts to develop an avirulent nonreverting pyrimidine auxotroph strain. Additionally, to functionally address the role of the pyrimidine salvage pathway the uridine phosphorylase (UP) salvage activity was knocked out and a double knockout of UP and OMPDC was also constructed. The nonreverting DeltaOMPDC, DeltaUP, and DeltaOMPDCDeltaUP knockout strains were evaluated for pyrimidine auxotrophy, for attenuation of virulence, and for their ability to elicit potent immunity to reinfection. The DeltaUP knockout strain was replication competent and virulent. In contrast, the DeltaOMPDC and DeltaOMPDCDeltaUP strains were uracil auxotrophs that rapidly lost their viability during pyrimidine starvation. Replication of the DeltaOMPDC strain, but not the DeltaOMPDCDeltaUP strain, was also partially rescued in vitro with uridine or cytidine supplementation. Compared to their hypervirulent parental type I strain, the DeltaOMPDC and DeltaOMPDCDeltaUP knockout strains exhibited extreme attenuation in murine virulence ( approximately 8 logs). Genetic complementation of the DeltaOMPDC strain using a functional OMPDC allele restored normal replication and type I parental strain virulence phenotypes. A single immunization of mice with either the live critically attenuated DeltaOMPDC or the DeltaOMPDCDeltaUP knockout strain effectively induced potent protective immunity to lethal challenge infection. The avirulent nonreverting DeltaOMPDC and DeltaOMPDCDeltaUP strains provide new tools for the dissection of host response to infection and promising candidates for safe and effective Th1 vaccine platforms that can be easily genetically engineered.
PMID: 20605980 [PubMed - as supplied by publisher]
Wednesday, July 07, 2010
Could a brain parasite found in cats help soccer teams win at the World Cup?
"What if I told you that last week I predicted all eight winners of a round of the World Cup? And that instead of rankings or divination all I did was look up how many people in each team's home country had a tiny parasite lurking in their amygdalas? Would you believe me? A decade ago, Discover Magazine concluded that parasites ruled the world, and now I'm going to try to tell you that, at the very least, parasites rule the World Cup."
Read full article here.
Read full article here.
Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis
Br J Ophthalmol. 2010 Jul 3. [Epub ahead of print]
Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis
Silveira C, Vallochi AL, Rodrigues da Silva U, Muccioli C, Holland GN, Nussenblatt RB, Belfort R, Rizzo LV.
Escola Paulista de Medicina-Federal University of São Paulo, São Paulo, Brazil.
Abstract
Background and aims Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients. Methods Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA. Results The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis. Conclusions The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.
PMID: 20601663 [PubMed - as supplied by publisher]
Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis
Silveira C, Vallochi AL, Rodrigues da Silva U, Muccioli C, Holland GN, Nussenblatt RB, Belfort R, Rizzo LV.
Escola Paulista de Medicina-Federal University of São Paulo, São Paulo, Brazil.
Abstract
Background and aims Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients. Methods Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA. Results The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis. Conclusions The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.
PMID: 20601663 [PubMed - as supplied by publisher]
Friday, July 02, 2010
Virulence of Toxoplasma gondii Is Associated with Distinct Dendritic Cell Responses and Reduced Numbers of Activated CD8+ T Cells
J Immunol. 2010 Jun 30. [Epub ahead of print]
Virulence of Toxoplasma gondii Is Associated with Distinct Dendritic Cell Responses and Reduced Numbers of Activated CD8+ T Cells
Tait ED, Jordan KA, Dupont CD, Harris TH, Gregg B, Wilson EH, Pepper M, Dzierszinski F, Roos DS, Hunter CA.
Department of Pathobiology and.
Abstract
The Toxoplasma gondii population consists of multiple strains, defined by genotype and virulence. Previous studies have established that protective immunity to this organism is mediated by IL-12, which drives T cells to produce IFN-gamma. Paradoxically, although type I and type II strains of T. gondii both induce IL-12 and IFN-gamma in the mouse, type I parasites are lethal, whereas type II strains establish chronic infection. The cellular basis for these strain-dependent differences remains unclear. To better understand these events, the CD8(+) T cell and dendritic cell (DC) responses to transgenic, OVA-expressing type I RH (RH OVA) and type II Prugniuad (Pru OVA) parasites were examined. Pru OVA-infected mice developed a robust DC response at the site of infection and the draining lymph node and generated a population of endogenous OVA-specific CD8(+) T cells. In contrast, RH OVA-infected mice had fewer DCs and OVA-specific CD8(+) T cells. RH OVA-infected mice given preactivated OVA-specific CD8(+) T cells were protected, suggesting that reduced DC-derived signals contributed to the low OVA-specific CD8(+) T cell numbers observed during type I infection. Indeed, DC depletion prior to Pru OVA infection resulted in a failure to generate activated OVA-specific CD8(+) T cells, and IL-12p70 treatment during RH OVA infection modestly increased the number of Ag-specific cells. Together, these data are consistent with a model of immunity to T. gondii in which strain-dependent DC responses shape the generation of Ag-specific CD8(+) T cells and determine the outcome of infection.
PMID: 20592284 [PubMed - as supplied by publisher]
Virulence of Toxoplasma gondii Is Associated with Distinct Dendritic Cell Responses and Reduced Numbers of Activated CD8+ T Cells
Tait ED, Jordan KA, Dupont CD, Harris TH, Gregg B, Wilson EH, Pepper M, Dzierszinski F, Roos DS, Hunter CA.
Department of Pathobiology and.
Abstract
The Toxoplasma gondii population consists of multiple strains, defined by genotype and virulence. Previous studies have established that protective immunity to this organism is mediated by IL-12, which drives T cells to produce IFN-gamma. Paradoxically, although type I and type II strains of T. gondii both induce IL-12 and IFN-gamma in the mouse, type I parasites are lethal, whereas type II strains establish chronic infection. The cellular basis for these strain-dependent differences remains unclear. To better understand these events, the CD8(+) T cell and dendritic cell (DC) responses to transgenic, OVA-expressing type I RH (RH OVA) and type II Prugniuad (Pru OVA) parasites were examined. Pru OVA-infected mice developed a robust DC response at the site of infection and the draining lymph node and generated a population of endogenous OVA-specific CD8(+) T cells. In contrast, RH OVA-infected mice had fewer DCs and OVA-specific CD8(+) T cells. RH OVA-infected mice given preactivated OVA-specific CD8(+) T cells were protected, suggesting that reduced DC-derived signals contributed to the low OVA-specific CD8(+) T cell numbers observed during type I infection. Indeed, DC depletion prior to Pru OVA infection resulted in a failure to generate activated OVA-specific CD8(+) T cells, and IL-12p70 treatment during RH OVA infection modestly increased the number of Ag-specific cells. Together, these data are consistent with a model of immunity to T. gondii in which strain-dependent DC responses shape the generation of Ag-specific CD8(+) T cells and determine the outcome of infection.
PMID: 20592284 [PubMed - as supplied by publisher]
Versatility in the acquisition of energy and carbon sources by the Apicomplexa
Biol Cell. 2010 Apr 23;102(8):435-45.
Versatility in the acquisition of energy and carbon sources by the Apicomplexa
Polonais V, Soldati-Favre D.
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Centre Médical Universitaire (CMU), 1 rue Michel-Servet, 1211 Geneva 4, Switzerland.
Members of the phylum Apicomplexa are motile and rapidly dividing intracellular parasites, able to occupy a large spectrum of niches by infecting diverse hosts and invading various cell types. As obligate intracellular parasites, most apicomplexans only survive for a short period extracellularly, and, during this time, have a high energy demand to power gliding motility and invasion into new host cells. Similarly, these fast-replicating intracellular parasites are critically dependent on host-cell nutrients as energy and carbon sources, noticeably for the extensive membrane biogenesis imposed during growth and division. To access host-cell metabolites, the apicomplexans Toxoplasma gondii and Plasmodium falciparum have evolved strategies that exquisitely reflect adaptation to their respective niches. In the present review, we summarize and compare some recent findings regarding the energetic metabolism and carbon sources used by these two genetically tractable apicomplexans during host-cell invasion and intracellular growth and replication.
PMID: 20586726 [PubMed - in process]
Versatility in the acquisition of energy and carbon sources by the Apicomplexa
Polonais V, Soldati-Favre D.
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Centre Médical Universitaire (CMU), 1 rue Michel-Servet, 1211 Geneva 4, Switzerland.
Members of the phylum Apicomplexa are motile and rapidly dividing intracellular parasites, able to occupy a large spectrum of niches by infecting diverse hosts and invading various cell types. As obligate intracellular parasites, most apicomplexans only survive for a short period extracellularly, and, during this time, have a high energy demand to power gliding motility and invasion into new host cells. Similarly, these fast-replicating intracellular parasites are critically dependent on host-cell nutrients as energy and carbon sources, noticeably for the extensive membrane biogenesis imposed during growth and division. To access host-cell metabolites, the apicomplexans Toxoplasma gondii and Plasmodium falciparum have evolved strategies that exquisitely reflect adaptation to their respective niches. In the present review, we summarize and compare some recent findings regarding the energetic metabolism and carbon sources used by these two genetically tractable apicomplexans during host-cell invasion and intracellular growth and replication.
PMID: 20586726 [PubMed - in process]
Congenital toxoplasmosis in France in 2007: first results from a national surveillance system
Euro Surveill. 2010 Jun 24;15(25). pii: 19600.
Congenital toxoplasmosis in France in 2007: first results from a national surveillance system
Villena I, Ancelle T, Delmas C, Garcia P, Brezin AP, Thulliez P, Wallon M, King L, Goulet V; Toxosurv network and National Reference Centre for Toxoplasmosis.
Collaborators (54)Totet A, Cimon B, Scherrer E, Couprie B, Nevez G, Quinio D, Duhamel C, Carme B, Bonnin A, Cuisenier B, Dalle F, Brenier-Pinchart MP, Fricker-Hidalgo H, Pelloux H, Azia S, Morel A, Delhaes L, Ajzenberg D, Dardé ML, Wallon M, Franck J, Piarroux R, Desbois N, Bastien P, Pratlong F, Machouart M, Gay-Andrieu F, Ferret N, Marty P, Houze S, Ancelle T, Yera H, Derouin F, Garin JF, Menotti J, Brun S, Paris L, Godineau N, Roux P, Rodier MH, Aubert D, Chemla C, Villena I, Gangneux F, Favennec L, Flori P, Candolfi E, Filisetti D, Villard O, Bessières MH, Cassaing S, Duong TH, Costa JM, Denoyel G.
National Reference Centre for Toxoplasmosis, Maison Blanche Hospital, University Reims Champagne-Ardenne, France. ivillena@chu-reims.fr
Abstract
When immunocompetent people become infected with the parasite Toxoplasma gondii, the disease is generally asymptomatic. However, transplacental transmission of T. gondii may lead to severe congenital infection including in utero abortion, foetal death, or neurological or ocular damage of the foetus. France has had a national programme to prevent congenital toxoplasmosis since 1978. However, although estimated seroprevalence in pregnant women has fallen from 84% in the 1960s to 44% in 2003, no reliable data have been available on the annual number of cases of congenital toxoplasmosis or the severity of infection. In 2006, the French National Institute for Public Health Surveillance (Institut de Veille Sanitaire) and the National Reference Centre for Toxoplasmosis recommended that a national laboratory-based surveillance system be used for the surveillance of the disease. In 2007, 31 laboratories reported at least one congenital case through the surveillance system, giving a total of 272 cases. A total of 11 terminations of pregnancy were reported (six abortions and five foetal deaths). Of the live-born cases, 206 were asymptomatic, 28 were symptomatic and seven had a severe form of the disease. As there were 818,700 births in France and French overseas departments in 2007, the overall prevalence of congenital toxoplasmosis observed that year was 3.3 (95% confidence interval (CI): 2.9 to 3.7) per 10,000 live births and the incidence rate of the disease at birth was 2.9 (95% CI: 2.5 to 3.2) per 10,000 live births; the estimated incidence rate of symptomatic congenital toxoplasmosis was 0.34 (95% CI: 0.2 to 0.5) cases per 10,000 live births.
PMID: 20587361 [PubMed - in process]
Congenital toxoplasmosis in France in 2007: first results from a national surveillance system
Villena I, Ancelle T, Delmas C, Garcia P, Brezin AP, Thulliez P, Wallon M, King L, Goulet V; Toxosurv network and National Reference Centre for Toxoplasmosis.
Collaborators (54)Totet A, Cimon B, Scherrer E, Couprie B, Nevez G, Quinio D, Duhamel C, Carme B, Bonnin A, Cuisenier B, Dalle F, Brenier-Pinchart MP, Fricker-Hidalgo H, Pelloux H, Azia S, Morel A, Delhaes L, Ajzenberg D, Dardé ML, Wallon M, Franck J, Piarroux R, Desbois N, Bastien P, Pratlong F, Machouart M, Gay-Andrieu F, Ferret N, Marty P, Houze S, Ancelle T, Yera H, Derouin F, Garin JF, Menotti J, Brun S, Paris L, Godineau N, Roux P, Rodier MH, Aubert D, Chemla C, Villena I, Gangneux F, Favennec L, Flori P, Candolfi E, Filisetti D, Villard O, Bessières MH, Cassaing S, Duong TH, Costa JM, Denoyel G.
National Reference Centre for Toxoplasmosis, Maison Blanche Hospital, University Reims Champagne-Ardenne, France. ivillena@chu-reims.fr
Abstract
When immunocompetent people become infected with the parasite Toxoplasma gondii, the disease is generally asymptomatic. However, transplacental transmission of T. gondii may lead to severe congenital infection including in utero abortion, foetal death, or neurological or ocular damage of the foetus. France has had a national programme to prevent congenital toxoplasmosis since 1978. However, although estimated seroprevalence in pregnant women has fallen from 84% in the 1960s to 44% in 2003, no reliable data have been available on the annual number of cases of congenital toxoplasmosis or the severity of infection. In 2006, the French National Institute for Public Health Surveillance (Institut de Veille Sanitaire) and the National Reference Centre for Toxoplasmosis recommended that a national laboratory-based surveillance system be used for the surveillance of the disease. In 2007, 31 laboratories reported at least one congenital case through the surveillance system, giving a total of 272 cases. A total of 11 terminations of pregnancy were reported (six abortions and five foetal deaths). Of the live-born cases, 206 were asymptomatic, 28 were symptomatic and seven had a severe form of the disease. As there were 818,700 births in France and French overseas departments in 2007, the overall prevalence of congenital toxoplasmosis observed that year was 3.3 (95% confidence interval (CI): 2.9 to 3.7) per 10,000 live births and the incidence rate of the disease at birth was 2.9 (95% CI: 2.5 to 3.2) per 10,000 live births; the estimated incidence rate of symptomatic congenital toxoplasmosis was 0.34 (95% CI: 0.2 to 0.5) cases per 10,000 live births.
PMID: 20587361 [PubMed - in process]
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