J Infect Dis. 2012 Apr 26. [Epub ahead of print]
PD-1 mediated attrition of polyfunctional memory CD8+ T cells in chronic Toxoplasma infection
Bhadra R, Gigley JP, Khan IA.
Source
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, USA.
Abstract
We reported earlier that during chronic toxoplasmosis CD8(+) T cells become functionally exhausted with concomitant PD-1 up-regulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8(+) T cells which renders them susceptible to apoptosis. In vitro blockade of PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and IFNγ(+)GranzymeB(-) memory but not effector CD8(+) T cells. In summary, the present report underscores the critical role of the PD-1-PD-L1 pathway in mediating attrition of this important CD8(+) T cell subset and addresses the mechanistic basis of how αPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections.
PMID: 22539813 [PubMed - as supplied by publisher]
Sunday, April 29, 2012
Wednesday, April 25, 2012
Toxoplasma gondii Actively Inhibits Neuronal Function in Chronically Infected Mice
PLoS One. 2012;7(4):e35516. Epub 2012 Apr 18.
Toxoplasma gondii Actively Inhibits Neuronal Function in Chronically Infected Mice
Haroon F, Händel U, Angenstein F, Goldschmidt J, Kreutzmann P, Lison H, Fischer KD, Scheich H, Wetzel W, Schlüter D, Budinger E.
Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany.
Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+)) imaging studies revealed that tachyzoites actively manipulated Ca(2+) signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+) uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+) stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host.
PMID: 22530040 [PubMed - in process]
Toxoplasma gondii Actively Inhibits Neuronal Function in Chronically Infected Mice
Haroon F, Händel U, Angenstein F, Goldschmidt J, Kreutzmann P, Lison H, Fischer KD, Scheich H, Wetzel W, Schlüter D, Budinger E.
Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany.
Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+)) imaging studies revealed that tachyzoites actively manipulated Ca(2+) signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+) uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+) stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host.
PMID: 22530040 [PubMed - in process]
Toxoplasma gondii tachyzoites cross retinal endothelium assisted by intercellular adhesion molecule-1 in vitro
Immunol Cell Biol. 2012 Apr 24. doi: 10.1038/icb.2012.21. [Epub ahead of print]
Toxoplasma gondii tachyzoites cross retinal endothelium assisted by intercellular adhesion molecule-1 in vitro
Furtado JM, Bharadwaj AS, Chipps TJ, Pan Y, Ashander LM, Smith JR.
Source
Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
Abstract
Retinal infection is the most common clinical manifestation of toxoplasmosis. The route by which circulating Toxoplasma gondii tachyzoites cross the vascular endothelium to enter the human retina is unknown. Convincing studies using murine encephalitis models have strongly implicated leukocyte taxis as one pathway used by the parasite to access target organs. To establish whether tachyzoites might also interact directly with vascular endothelium, we populated a transwell system with human ocular endothelial cells. Human retinal endothelial monolayers permitted transmigration of tachyzoites of RH and three natural isolate strains. Antibody blockade of intercellular adhesion molecule-1 significantly reduced this migration, but did not impact tachyzoite movement across an endothelial monolayer derived from the choroid, which lies adjacent to the retina within the eye. In demonstrating that tachyzoites are capable of independent migration across human vascular endothelium in vitro, this study carries implications for the development of therapeutics aimed at preventing access of T. gondii to the retina.Immunology and Cell Biology advance online publication, 24 April 2012; doi:10.1038/icb.2012.21.
PMID: 22525368 [PubMed - as supplied by publisher]
Toxoplasma gondii tachyzoites cross retinal endothelium assisted by intercellular adhesion molecule-1 in vitro
Furtado JM, Bharadwaj AS, Chipps TJ, Pan Y, Ashander LM, Smith JR.
Source
Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
Abstract
Retinal infection is the most common clinical manifestation of toxoplasmosis. The route by which circulating Toxoplasma gondii tachyzoites cross the vascular endothelium to enter the human retina is unknown. Convincing studies using murine encephalitis models have strongly implicated leukocyte taxis as one pathway used by the parasite to access target organs. To establish whether tachyzoites might also interact directly with vascular endothelium, we populated a transwell system with human ocular endothelial cells. Human retinal endothelial monolayers permitted transmigration of tachyzoites of RH and three natural isolate strains. Antibody blockade of intercellular adhesion molecule-1 significantly reduced this migration, but did not impact tachyzoite movement across an endothelial monolayer derived from the choroid, which lies adjacent to the retina within the eye. In demonstrating that tachyzoites are capable of independent migration across human vascular endothelium in vitro, this study carries implications for the development of therapeutics aimed at preventing access of T. gondii to the retina.Immunology and Cell Biology advance online publication, 24 April 2012; doi:10.1038/icb.2012.21.
PMID: 22525368 [PubMed - as supplied by publisher]
Tuesday, April 24, 2012
Intramembrane proteolysis of Toxoplasma apical membrane antigen 1 facilitates host-cell invasion but is dispensable for replication
Proc Natl Acad Sci U S A. 2012
Apr 20. [Epub ahead of print]
Intramembrane proteolysis of Toxoplasma apical membrane antigen 1 facilitates host-cell invasion but is dispensable for replication.
SourceDepartment of Microbiology and Molecular Genetics, University of Vermont,
Burlington, VT 05405.
Abstract
Apical membrane antigen 1 (AMA1) is a conserved transmembrane adhesin of
apicomplexan parasites that plays an important role in host-cell invasion.
Toxoplasma gondii AMA1 (TgAMA1) is secreted onto the parasite surface and
subsequently released by proteolytic cleavage within its transmembrane domain.
To elucidate the function of TgAMA1 intramembrane proteolysis, we used a
heterologous cleavage assay to characterize the determinants within the TgAMA1
transmembrane domain (ALIAGLAVGGVLLLALLGGGCYFA) that govern its processing.
Quantitative analysis revealed that the TgAMA1(L/G) mutation enhanced cleavage
by 13-fold compared with wild type. In contrast, the TgAMA1(AG/FF) mutation
reduced cleavage by 30-fold, whereas the TgAMA1(GG/FF) mutation had a minor
effect on proteolysis; mutating both motifs in a quadruple mutant blocked
cleavage completely. We then complemented a TgAMA1 conditional knockout parasite
line with plasmids expressing these TgAMA1 variants. Contrary to expectation,
variants that increased or decreased TgAMA1 processing by >10-fold had no
phenotypic consequences, revealing that the levels of rhomboid proteolysis in
parasites are not delicately balanced. Only parasites transgenically expressing
or carrying a true knock-in allele of the uncleavable TgAMA1(AG/FF+GG/FF) mutant
showed a growth defect, which resulted from inhibiting invasion without
perturbing intracellular replication. These data demonstrate that TgAMA1
cleavage plays a role in invasion, but refute a recently proposed model in which
parasite replication within the host cell is regulated by intramembrane
proteolysis of TgAMA1.
- PMID: 22523242
The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system
Horm Behav. 2012 Apr 11. [Epub ahead of
print]
The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system.
Kaushik M, Lamberton PH, Webster JP.
Abstract
Behavioural and neurophysiological traits and responses associated with anxiety and predation-related fear have been well documented in rodent models. Certain parasites and pathogens which rely on predation for transmission appear able to manipulate these, often innate, traits to increase the likelihood of their life-cycle being completed. This can occur through a range of mechanisms, such as alteration of hormonal and neurotransmitter communication and/or direct interference with the neurons and brain regions that mediate behavioural expression. Whilst some post-infection behavioural changes may reflect 'general sickness' or a pathological by-product of infection, others may have a specific adaptive advantage to the parasite and be indicative of active manipulation of host behaviour. Here we review the key mechanisms by which anxiety and predation-related fears are controlled in mammals, before exploring evidence for how some infectious agents may manipulate these mechanisms. The protozoan Toxoplasma gondii, the causative agent of toxoplasmosis, is focused on as a prime example. Selective pressures appear to have allowed this parasite to evolve strategies to alter the behaviour in its natural intermediate rodent host. Latent infection has also been associated with a range of altered behavioural profiles, from subtle to severe, in other secondary host species including humans. In addition to enhancing our knowledge of the evolution of parasite manipulation in general, to further our understanding of how and when these potential changes to human host behaviour occur, and how we may prevent or manage them, it is imperative to elucidate the associated mechanisms involved. This article is part of a Special Issue entitled Neuroendocrine-Immune Axis in Health and Disease. Copyright © 2012. Published by Elsevier Inc.
Behavioural and neurophysiological traits and responses associated with anxiety and predation-related fear have been well documented in rodent models. Certain parasites and pathogens which rely on predation for transmission appear able to manipulate these, often innate, traits to increase the likelihood of their life-cycle being completed. This can occur through a range of mechanisms, such as alteration of hormonal and neurotransmitter communication and/or direct interference with the neurons and brain regions that mediate behavioural expression. Whilst some post-infection behavioural changes may reflect 'general sickness' or a pathological by-product of infection, others may have a specific adaptive advantage to the parasite and be indicative of active manipulation of host behaviour. Here we review the key mechanisms by which anxiety and predation-related fears are controlled in mammals, before exploring evidence for how some infectious agents may manipulate these mechanisms. The protozoan Toxoplasma gondii, the causative agent of toxoplasmosis, is focused on as a prime example. Selective pressures appear to have allowed this parasite to evolve strategies to alter the behaviour in its natural intermediate rodent host. Latent infection has also been associated with a range of altered behavioural profiles, from subtle to severe, in other secondary host species including humans. In addition to enhancing our knowledge of the evolution of parasite manipulation in general, to further our understanding of how and when these potential changes to human host behaviour occur, and how we may prevent or manage them, it is imperative to elucidate the associated mechanisms involved. This article is part of a Special Issue entitled Neuroendocrine-Immune Axis in Health and Disease. Copyright © 2012. Published by Elsevier Inc.
PMID:
22521209
Monday, April 23, 2012
Which roles for autophagy in Toxoplasma gondii and related apicomplexan parasites?
Mol Biochem Parasitol. 2012 Apr 9. [Epub ahead of print]
Which roles for autophagy in Toxoplasma gondii and related apicomplexan parasites?
Besteiro S.
Source
DIMNP, UMR5235 CNRS, Universités de Montpellier 1 & 2, Montpellier 34095, France.
Abstract
Autophagy is a life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles called autophagosomes, and degraded after fusion with a lytic compartment. This process can be triggered under cellular stress conditions in order to recycle damaged organelles or provide nutrients to the cell, but may also be involved in cell remodelling during normal development. This catabolic process is conserved among most eukaryotes and characterisation of its molecular machinery has benefited greatly from functional genetic studies in yeast and mammalian models. Until recently, not much was known about the functions of autophagy in Apicomplexa, but recent data obtained in Toxoplasma have shed light on a very important role for this machinery, potentially at the crossroads between life and death decisions for the parasite. The possible roles for autophagy during the life cycles of other medically important apicomplexan parasites and the perspectives for discovering new drug targets in this pathway for combating these parasites are discussed in this review. Copyright © 2012. Published by Elsevier B.V.
PMID: 22515957 [PubMed - as supplied by publisher]
Which roles for autophagy in Toxoplasma gondii and related apicomplexan parasites?
Besteiro S.
Source
DIMNP, UMR5235 CNRS, Universités de Montpellier 1 & 2, Montpellier 34095, France.
Abstract
Autophagy is a life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles called autophagosomes, and degraded after fusion with a lytic compartment. This process can be triggered under cellular stress conditions in order to recycle damaged organelles or provide nutrients to the cell, but may also be involved in cell remodelling during normal development. This catabolic process is conserved among most eukaryotes and characterisation of its molecular machinery has benefited greatly from functional genetic studies in yeast and mammalian models. Until recently, not much was known about the functions of autophagy in Apicomplexa, but recent data obtained in Toxoplasma have shed light on a very important role for this machinery, potentially at the crossroads between life and death decisions for the parasite. The possible roles for autophagy during the life cycles of other medically important apicomplexan parasites and the perspectives for discovering new drug targets in this pathway for combating these parasites are discussed in this review. Copyright © 2012. Published by Elsevier B.V.
PMID: 22515957 [PubMed - as supplied by publisher]
Saturday, April 14, 2012
Prematurity and Severity Are Associated With Toxoplasma gondii Alleles
Clin Infect Dis. 2012 Apr 11. [Epub ahead of print]
Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981-2009).
McLeod R, Boyer KM, Lee D, Mui E, Wroblewski K, Karrison T, Noble AG, Withers S, Swisher CN, Heydemann PT, Sautter M, Babiarz J, Rabiah P, Meier P, Grigg ME; the Toxoplasmosis Study Group.
SourceDepartments ofOphthalmology and Visual Sciences.
Abstract
Background. Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types.Methods. ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined.Results. Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment.Conclusions. Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment.Clinical Trials Registration. NCT00004317.
PMID: 22499837 [PubMed - as supplied by publisher]
Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981-2009).
McLeod R, Boyer KM, Lee D, Mui E, Wroblewski K, Karrison T, Noble AG, Withers S, Swisher CN, Heydemann PT, Sautter M, Babiarz J, Rabiah P, Meier P, Grigg ME; the Toxoplasmosis Study Group.
SourceDepartments ofOphthalmology and Visual Sciences.
Abstract
Background. Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types.Methods. ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined.Results. Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment.Conclusions. Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment.Clinical Trials Registration. NCT00004317.
PMID: 22499837 [PubMed - as supplied by publisher]
Thursday, April 12, 2012
Cactin is essential for G1 progression in Toxoplasma gondii
Mol Microbiol. 2012 Apr 9. doi: 10.1111/j.1365-2958.2012.08044.x. [Epub ahead of print]
Cactin is essential for G1 progression in Toxoplasma gondii.
Szatanek T, Anderson-White BR, Faugno-Fusci DM, White M, Saeij JP, Gubbels MJ.
SourceDepartment of Biology, Boston College, Chestnut Hill, MA 02467, USA Departments of Molecular Medicine & Global Health, Florida Center for Drug Discovery and Innovation, Colleges of Medicine & Public Health, University of South Florida, Tampa, FL 33612, USA Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract
Toxoplasma gondii is an obligate intracellular protozoan parasite whose rapid lytic replication cycles define its pathogenicity. We identified a temperature-sensitive growth mutant, FV-P6, which irreversibly arrests before the middle of the G1 stage of the tachyzoite cell cycle. This arrest is caused by a point mutation in a gene conserved across eukaryotes, Cactin, whose product localizes to the nucleus. To elucidate the role of TgCactin we performed genome-wide expression profiling. Besides the expected G1 expression profile, many genes associated with the extracellular state as well as with the bradyzoite cyst stage were identified. Consistent with these profiles were the expression of AP2 transcription factors typically associated with extracellular and bradyzoite stage parasites. This suggests a role for TgCactin in control of gene expression. As TgCactin does not contain any functionally defined domains we reasoned TgCactin exerts its function through interactions with other proteins. In support of this model we demonstrated that TgCactin is present in a protein complex and can oligomerize. Taken together, these results suggest that TgCactin acts as a pivotal protein potentially regulating gene expression at several transition points in parasite development.
© 2012 Blackwell Publishing Ltd.
PMID: 22486860 [PubMed - as supplied by publisher]
Cactin is essential for G1 progression in Toxoplasma gondii.
Szatanek T, Anderson-White BR, Faugno-Fusci DM, White M, Saeij JP, Gubbels MJ.
SourceDepartment of Biology, Boston College, Chestnut Hill, MA 02467, USA Departments of Molecular Medicine & Global Health, Florida Center for Drug Discovery and Innovation, Colleges of Medicine & Public Health, University of South Florida, Tampa, FL 33612, USA Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract
Toxoplasma gondii is an obligate intracellular protozoan parasite whose rapid lytic replication cycles define its pathogenicity. We identified a temperature-sensitive growth mutant, FV-P6, which irreversibly arrests before the middle of the G1 stage of the tachyzoite cell cycle. This arrest is caused by a point mutation in a gene conserved across eukaryotes, Cactin, whose product localizes to the nucleus. To elucidate the role of TgCactin we performed genome-wide expression profiling. Besides the expected G1 expression profile, many genes associated with the extracellular state as well as with the bradyzoite cyst stage were identified. Consistent with these profiles were the expression of AP2 transcription factors typically associated with extracellular and bradyzoite stage parasites. This suggests a role for TgCactin in control of gene expression. As TgCactin does not contain any functionally defined domains we reasoned TgCactin exerts its function through interactions with other proteins. In support of this model we demonstrated that TgCactin is present in a protein complex and can oligomerize. Taken together, these results suggest that TgCactin acts as a pivotal protein potentially regulating gene expression at several transition points in parasite development.
© 2012 Blackwell Publishing Ltd.
PMID: 22486860 [PubMed - as supplied by publisher]
Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism
Dev Neurobiol. 2012 Apr 5. doi: 10.1002/dneu.22024. [Epub ahead of print]
Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.
Brown AS.
SourceProfessor of Clinical Psychiatry and Clinical Epidemiology, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY, USA. asb11@columbia.edu.
Abstract
In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained following biomarker assays of archived maternal sera and by obstetric records was related to an elevated risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, elevated toxoplasma antibody, genital/reproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.
Copyright © 2012 Wiley Periodicals, Inc.
PMID: 22488761 [PubMed - as supplied by publisher]
Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.
Brown AS.
SourceProfessor of Clinical Psychiatry and Clinical Epidemiology, College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY, USA. asb11@columbia.edu.
Abstract
In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained following biomarker assays of archived maternal sera and by obstetric records was related to an elevated risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, elevated toxoplasma antibody, genital/reproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.
Copyright © 2012 Wiley Periodicals, Inc.
PMID: 22488761 [PubMed - as supplied by publisher]
Epidemiology of and diagnostic strategies for toxoplasmosis
Clin Microbiol Rev. 2012 Apr;25(2):264-96.
Epidemiology of and diagnostic strategies for toxoplasmosis.
Robert-Gangneux F, Dardé ML.
SourceAddress correspondence to Florence Robert-Gangneux, florence.robert-gangneux@univ-rennes1.fr.
Abstract
Summary: The apicomplexan parasite Toxoplasma gondii was discovered a little over 100 years ago, but knowledge of its biological life cycle and its medical importance has grown in the last 40 years. This obligate intracellular parasite was identified early as a pathogen responsible for congenital infection, but its clinical expression and the importance of reactivations of infections in immunocompromised patients were recognized later, in the era of organ transplantation and HIV infection. Recent knowledge of host cell-parasite interactions and of parasite virulence has brought new insights into the comprehension of the pathophysiology of infection. In this review, we focus on epidemiological and diagnostic aspects, putting them in perspective with current knowledge of parasite genotypes. In particular, we provide critical information on diagnostic methods according to the patient's background and discuss the implementation of screening tools for congenital toxoplasmosis according to health policies.
PMID: 22491772 [PubMed - in process]
Epidemiology of and diagnostic strategies for toxoplasmosis.
Robert-Gangneux F, Dardé ML.
SourceAddress correspondence to Florence Robert-Gangneux, florence.robert-gangneux@univ-rennes1.fr.
Abstract
Summary: The apicomplexan parasite Toxoplasma gondii was discovered a little over 100 years ago, but knowledge of its biological life cycle and its medical importance has grown in the last 40 years. This obligate intracellular parasite was identified early as a pathogen responsible for congenital infection, but its clinical expression and the importance of reactivations of infections in immunocompromised patients were recognized later, in the era of organ transplantation and HIV infection. Recent knowledge of host cell-parasite interactions and of parasite virulence has brought new insights into the comprehension of the pathophysiology of infection. In this review, we focus on epidemiological and diagnostic aspects, putting them in perspective with current knowledge of parasite genotypes. In particular, we provide critical information on diagnostic methods according to the patient's background and discuss the implementation of screening tools for congenital toxoplasmosis according to health policies.
PMID: 22491772 [PubMed - in process]
Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection
J Leukoc Biol. 2012 Apr 9. [Epub ahead of print]
Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection.
Chou DB, Sworder B, Bouladoux N, Roy CN, Uchida AM, Grigg M, Robey PG, Belkaid Y.
Source*Mucosal Immunology and.
Abstract
Inflammation alters hematopoiesis, often by decreasing erythropoiesis and enhancing myeloid output. The mechanisms behind these changes and how the BM stroma contributes to this process are active areas of research. In this study, we examine these questions in the setting of murine Toxoplasma gondii infection. Our data reveal that infection alters early myeloerythroid differentiation, blocking erythroid development beyond the Pre MegE stage, while expanding the GMP population. IL-6 was found to be a critical mediator of these differences, independent of hepcidin-induced iron restriction. Comparing the BM with the spleen showed that the hematopoietic response was driven by the local microenvironment, and BM chimeras demonstrated that radioresistant cells were the relevant source of IL-6 in vivo. Finally, direct ex vivo sorting revealed that VCAM(+)CD146(lo) BM stromal fibroblasts significantly increase IL-6 secretion after infection. These data suggest that BMSCs regulate the hematopoietic changes during inflammation via IL-6.
PMID: 22493080 [PubMed - as supplied by publisher]
Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection.
Chou DB, Sworder B, Bouladoux N, Roy CN, Uchida AM, Grigg M, Robey PG, Belkaid Y.
Source*Mucosal Immunology and.
Abstract
Inflammation alters hematopoiesis, often by decreasing erythropoiesis and enhancing myeloid output. The mechanisms behind these changes and how the BM stroma contributes to this process are active areas of research. In this study, we examine these questions in the setting of murine Toxoplasma gondii infection. Our data reveal that infection alters early myeloerythroid differentiation, blocking erythroid development beyond the Pre MegE stage, while expanding the GMP population. IL-6 was found to be a critical mediator of these differences, independent of hepcidin-induced iron restriction. Comparing the BM with the spleen showed that the hematopoietic response was driven by the local microenvironment, and BM chimeras demonstrated that radioresistant cells were the relevant source of IL-6 in vivo. Finally, direct ex vivo sorting revealed that VCAM(+)CD146(lo) BM stromal fibroblasts significantly increase IL-6 secretion after infection. These data suggest that BMSCs regulate the hematopoietic changes during inflammation via IL-6.
PMID: 22493080 [PubMed - as supplied by publisher]
Tuesday, April 10, 2012
Protein palmitoylation inhibition by 2-bromopalmitate alters gliding, host cell invasion and parasite morphology in Toxoplasma gondii
Mol Biochem Parasitol. 2012 Mar 30. [Epub ahead of print]
Protein palmitoylation inhibition by 2-bromopalmitate alters gliding, host cell invasion and parasite morphology in Toxoplasma gondii.
Alonso AM, Coceres VM, De Napoli MG, Nieto Guil AF, Angel SO, Corvi MM.
SourceLaboratorio de Parasitología Molecular, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH), UNSAM/CONICET, Chascomus, Argentina.
Abstract
Protein palmitoylation is the reversible covalent attachment of palmitic acid onto proteins. This post-translational modification has been shown to play a part in diverse processes such as signal transduction, cellular localization and regulation of protein activity. Although many aspects of protein palmitoylation have been identified in mammalian and yeast cells, little is known of this modification in Toxoplasma gondii. In order to determine the functional role of protein palmitoylation in T. gondii, tachyzoites were treated with the palmitoylation inhibitor 2-bromopalmitate (2-BP). Parasites treated with 2-BP displayed a significant increase in non-circular trails which were longer than those trails left by non-treated parasites. Furthermore, 2-BP treatment reduced the invasion process to the host cells. Long-term treatment of intracellular tachyzoites resulted in major changes in parasite morphology and shape in a dose-dependent manner. These results suggest that palmitoylation could be modifying proteins that are key players in gliding, invasion and cytoskeletal proteins in T. gondii.
Copyright © 2012. Published by Elsevier B.V.
PMID: 22484029 [PubMed - as supplied by publisher]
Protein palmitoylation inhibition by 2-bromopalmitate alters gliding, host cell invasion and parasite morphology in Toxoplasma gondii.
Alonso AM, Coceres VM, De Napoli MG, Nieto Guil AF, Angel SO, Corvi MM.
SourceLaboratorio de Parasitología Molecular, Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH), UNSAM/CONICET, Chascomus, Argentina.
Abstract
Protein palmitoylation is the reversible covalent attachment of palmitic acid onto proteins. This post-translational modification has been shown to play a part in diverse processes such as signal transduction, cellular localization and regulation of protein activity. Although many aspects of protein palmitoylation have been identified in mammalian and yeast cells, little is known of this modification in Toxoplasma gondii. In order to determine the functional role of protein palmitoylation in T. gondii, tachyzoites were treated with the palmitoylation inhibitor 2-bromopalmitate (2-BP). Parasites treated with 2-BP displayed a significant increase in non-circular trails which were longer than those trails left by non-treated parasites. Furthermore, 2-BP treatment reduced the invasion process to the host cells. Long-term treatment of intracellular tachyzoites resulted in major changes in parasite morphology and shape in a dose-dependent manner. These results suggest that palmitoylation could be modifying proteins that are key players in gliding, invasion and cytoskeletal proteins in T. gondii.
Copyright © 2012. Published by Elsevier B.V.
PMID: 22484029 [PubMed - as supplied by publisher]
Thursday, April 05, 2012
Simple and efficient model systems of screening anti-Toxoplasma drugs in vitro
Expert Opin Drug Discov. 2012 Mar;7(3):195-205. Epub 2012 Feb 13.
Simple and efficient model systems of screening anti-Toxoplasma drugs in vitro.
Jin C, Jung SY, Kim SY, Song HO, Park H.
Source1Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine , Iksan, Jeonbuk 570-749 , South Korea +82 63 850 6768 ; hyunpk@wonkwang.ac.kr.
Abstract
Introduction: A lot of in vitro technologies have been developed to screen drugs for toxoplasmosis, which is caused by Toxoplasma gondii and is one of the most serious infectious diseases in the world. However, developed screening methods still have limitation such as inaccuracy, labor-intensive and time-consuming procedure. Therefore, the development of simpler, more efficient and accurate high-throughput screening assay is needed. Areas covered: The present review gives the overview of in vitro screening technologies described in literatures so far including morphological assay, incorporation of [(3)H]uracil assay, enzyme-linked immunosorbent assay (ELISA), colorimetric microtiter assay (β-galactosidase assay), flow cytometric quantification assay, yellow fluorescent protein assay and cell viability assay. The authors discuss how these methods are efficient and/or limited for screening anti-T. gondii drugs. The authors further suggest brand-new technologies which are faster, simpler, more effective and available for high-throughput screening. Expert opinion: Options for clinical treatment of toxoplasmosis are currently very limited. Thus, more accurate in vitro screening methods must be established to identify the most effective anti-T. gondii drugs from random screening of compounds. At the same time, based on genome information, combination of an appropriate screening technology, combinatorial chemistry and computational biology may increase the efficiency of target-based drug discovery against T. gondii.
PMID: 22468951 [PubMed - in process]
Simple and efficient model systems of screening anti-Toxoplasma drugs in vitro.
Jin C, Jung SY, Kim SY, Song HO, Park H.
Source1Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine , Iksan, Jeonbuk 570-749 , South Korea +82 63 850 6768 ; hyunpk@wonkwang.ac.kr.
Abstract
Introduction: A lot of in vitro technologies have been developed to screen drugs for toxoplasmosis, which is caused by Toxoplasma gondii and is one of the most serious infectious diseases in the world. However, developed screening methods still have limitation such as inaccuracy, labor-intensive and time-consuming procedure. Therefore, the development of simpler, more efficient and accurate high-throughput screening assay is needed. Areas covered: The present review gives the overview of in vitro screening technologies described in literatures so far including morphological assay, incorporation of [(3)H]uracil assay, enzyme-linked immunosorbent assay (ELISA), colorimetric microtiter assay (β-galactosidase assay), flow cytometric quantification assay, yellow fluorescent protein assay and cell viability assay. The authors discuss how these methods are efficient and/or limited for screening anti-T. gondii drugs. The authors further suggest brand-new technologies which are faster, simpler, more effective and available for high-throughput screening. Expert opinion: Options for clinical treatment of toxoplasmosis are currently very limited. Thus, more accurate in vitro screening methods must be established to identify the most effective anti-T. gondii drugs from random screening of compounds. At the same time, based on genome information, combination of an appropriate screening technology, combinatorial chemistry and computational biology may increase the efficiency of target-based drug discovery against T. gondii.
PMID: 22468951 [PubMed - in process]
CONGENITAL INFECTION OF MICE WITH TOXOPLASMA GONDII INDUCES MINIMAL CHANGE IN BEHAVIOR AND NO CHANGE IN NEUROTRANSMITTER CONCENTRATIONS
J Parasitol. 2012 Apr 2. [Epub ahead of print]
CONGENITAL INFECTION OF MICE WITH TOXOPLASMA GONDII INDUCES MINIMAL CHANGE IN BEHAVIOR AND NO CHANGE IN NEUROTRANSMITTER CONCENTRATIONS.
Goodwin DG, Hrubec TC, Klein BG, Strobl JS, Werre SR, Han Q, Zajac AM, Lindsay DS.
SourceVirginia Polytechnical Institute and State University, Professor, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnical Institute and State University.
Abstract
Abstract We examined the effect of maternal Toxoplasma gondii infection on the behavior and neurotransmitter concentrations of congenitally infected CD-1 mice at 4 and 8 wk of age when latent tissue cysts would be present in their brains. Because of sex associated behavioral changes that develop during aging, infected female mice were compared to control female mice and infected male mice were compared with control male mice. Only the short term memory behavior (distance between goal box and first hole investigated) of male mice congenitally infected with T. gondii was significantly different (P<0.05) from non-infected control male mice at both 4 and 8 wks in the Barnes Maze test. The other parameters examined in the Barnes Maze test, functional observational battery tests, virtual cliff, visual placement, and activity tests were not significantly different (P>0.05) at 4 and 8 wks. Neurotransmitters and their metabolites (dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, norepinephrine, epinephrine, 3-methoxy-4-hydroxyphenylglycol, serotonin, and 5-hydroxyindoleacetic acid) concentrations in the frontal cortex and striatum were not different (P>0.05) between infected and control mice at 8 wk of age. The exact mechanism for the observed effect on short term memory in male mice is not known and further investigation may help elucidate the molecular mechanism associated with the proposed link between behavioral changes and T. gondii infection in animals. We were not able to confirm the widely held belief that changes in neurotransmitters result from chronic T. gondii infection of the brain.
PMID: 22468990 [PubMed - as supplied by publisher]
CONGENITAL INFECTION OF MICE WITH TOXOPLASMA GONDII INDUCES MINIMAL CHANGE IN BEHAVIOR AND NO CHANGE IN NEUROTRANSMITTER CONCENTRATIONS.
Goodwin DG, Hrubec TC, Klein BG, Strobl JS, Werre SR, Han Q, Zajac AM, Lindsay DS.
SourceVirginia Polytechnical Institute and State University, Professor, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnical Institute and State University.
Abstract
Abstract We examined the effect of maternal Toxoplasma gondii infection on the behavior and neurotransmitter concentrations of congenitally infected CD-1 mice at 4 and 8 wk of age when latent tissue cysts would be present in their brains. Because of sex associated behavioral changes that develop during aging, infected female mice were compared to control female mice and infected male mice were compared with control male mice. Only the short term memory behavior (distance between goal box and first hole investigated) of male mice congenitally infected with T. gondii was significantly different (P<0.05) from non-infected control male mice at both 4 and 8 wks in the Barnes Maze test. The other parameters examined in the Barnes Maze test, functional observational battery tests, virtual cliff, visual placement, and activity tests were not significantly different (P>0.05) at 4 and 8 wks. Neurotransmitters and their metabolites (dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, norepinephrine, epinephrine, 3-methoxy-4-hydroxyphenylglycol, serotonin, and 5-hydroxyindoleacetic acid) concentrations in the frontal cortex and striatum were not different (P>0.05) between infected and control mice at 8 wk of age. The exact mechanism for the observed effect on short term memory in male mice is not known and further investigation may help elucidate the molecular mechanism associated with the proposed link between behavioral changes and T. gondii infection in animals. We were not able to confirm the widely held belief that changes in neurotransmitters result from chronic T. gondii infection of the brain.
PMID: 22468990 [PubMed - as supplied by publisher]
Toxoplasma gondii Infection in the Brain Inhibits Neuronal Degeneration and Learning and Memory Impairments in a Murine Model of Alzheimer's Disease
PLoS One. 2012;7(3):e33312. Epub 2012 Mar 21.
Toxoplasma gondii Infection in the Brain Inhibits Neuronal Degeneration and Learning and Memory Impairments in a Murine Model of Alzheimer's Disease.
Jung BK, Pyo KH, Shin KY, Hwang YS, Lim H, Lee SJ, Moon JH, Lee SH, Suh YH, Chai JY, Shin EH.
SourceDepartment of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea.
Abstract
Immunosuppression is a characteristic feature of Toxoplasma gondii-infected murine hosts. The present study aimed to determine the effect of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of Alzheimer's disease (AD) in Tg2576 AD mice. Mice were infected with a cyst-forming strain (ME49) of T. gondii, and levels of inflammatory mediators (IFN-γ and nitric oxide), anti-inflammatory cytokines (IL-10 and TGF-β), neuronal damage, and β-amyloid plaque deposition were examined in brain tissues and/or in BV-2 microglial cells. In addition, behavioral tests, including the water maze and Y-maze tests, were performed on T. gondii-infected and uninfected Tg2576 mice. Results revealed that whereas the level of IFN-γ was unchanged, the levels of anti-inflammatory cytokines were significantly higher in T. gondii-infected mice than in uninfected mice, and in BV-2 cells treated with T. gondii lysate antigen. Furthermore, nitrite production from primary cultured brain microglial cells and BV-2 cells was reduced by the addition of T. gondii lysate antigen (TLA), and β-amyloid plaque deposition in the cortex and hippocampus of Tg2576 mouse brains was remarkably lower in T. gondii-infected AD mice than in uninfected controls. In addition, water maze and Y-maze test results revealed retarded cognitive capacities in uninfected mice as compared with infected mice. These findings demonstrate the favorable effects of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of AD in Tg2576 mice.
PMID: 22470449 [PubMed - in process]
Toxoplasma gondii Infection in the Brain Inhibits Neuronal Degeneration and Learning and Memory Impairments in a Murine Model of Alzheimer's Disease.
Jung BK, Pyo KH, Shin KY, Hwang YS, Lim H, Lee SJ, Moon JH, Lee SH, Suh YH, Chai JY, Shin EH.
SourceDepartment of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea.
Abstract
Immunosuppression is a characteristic feature of Toxoplasma gondii-infected murine hosts. The present study aimed to determine the effect of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of Alzheimer's disease (AD) in Tg2576 AD mice. Mice were infected with a cyst-forming strain (ME49) of T. gondii, and levels of inflammatory mediators (IFN-γ and nitric oxide), anti-inflammatory cytokines (IL-10 and TGF-β), neuronal damage, and β-amyloid plaque deposition were examined in brain tissues and/or in BV-2 microglial cells. In addition, behavioral tests, including the water maze and Y-maze tests, were performed on T. gondii-infected and uninfected Tg2576 mice. Results revealed that whereas the level of IFN-γ was unchanged, the levels of anti-inflammatory cytokines were significantly higher in T. gondii-infected mice than in uninfected mice, and in BV-2 cells treated with T. gondii lysate antigen. Furthermore, nitrite production from primary cultured brain microglial cells and BV-2 cells was reduced by the addition of T. gondii lysate antigen (TLA), and β-amyloid plaque deposition in the cortex and hippocampus of Tg2576 mouse brains was remarkably lower in T. gondii-infected AD mice than in uninfected controls. In addition, water maze and Y-maze test results revealed retarded cognitive capacities in uninfected mice as compared with infected mice. These findings demonstrate the favorable effects of the immunosuppression induced by T. gondii infection on the pathogenesis and progression of AD in Tg2576 mice.
PMID: 22470449 [PubMed - in process]
ROS-triggered trophoblast apoptosis is initiated by ER stress via activation of caspase12, CHOP and the JNK pathway in Toxoplasma gondii infection
Infect Immun. 2012 Apr 2. [Epub ahead of print]
ROS-triggered trophoblast apoptosis is initiated by ER stress via activation of caspase12, CHOP and the JNK pathway in Toxoplasma gondii infection in mice.
Xu X, Liu T, Zhang A, Huo X, Luo Q, Chen Z, Yu L, Li Q, Liu L, Lun Z, Shen J.
SourceAnhui Provincial Laboratories of Pathogen Biology and Zoonoses; Department of Microbiology and Parasitology, Anhui Medical University, Hefei, China.
Abstract
Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH-strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress and subsequent apoptosis of placental trophoblasts. PCR Array analysis of 84 oxidative stress-related genes demonstrated that twenty-seven genes were up-regulated at least 2-fold and that nine genes were down-regulated at least 2-fold in the T.gondii infection group, compared with the control group. The expression of NADPH oxidase 1(Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-OHdG increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress(ERS)markers, followed by cleavage of caspase-12, activation of ASK1/JNK and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The up-regulation of Nox1 was contact-dependent and preceded the increase in levels of ERS markers and the activation of the pro-apoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase12, CHOP and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts.
PMID: 22473610 [PubMed - as supplied by publisher]
ROS-triggered trophoblast apoptosis is initiated by ER stress via activation of caspase12, CHOP and the JNK pathway in Toxoplasma gondii infection in mice.
Xu X, Liu T, Zhang A, Huo X, Luo Q, Chen Z, Yu L, Li Q, Liu L, Lun Z, Shen J.
SourceAnhui Provincial Laboratories of Pathogen Biology and Zoonoses; Department of Microbiology and Parasitology, Anhui Medical University, Hefei, China.
Abstract
Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH-strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress and subsequent apoptosis of placental trophoblasts. PCR Array analysis of 84 oxidative stress-related genes demonstrated that twenty-seven genes were up-regulated at least 2-fold and that nine genes were down-regulated at least 2-fold in the T.gondii infection group, compared with the control group. The expression of NADPH oxidase 1(Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-OHdG increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress(ERS)markers, followed by cleavage of caspase-12, activation of ASK1/JNK and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The up-regulation of Nox1 was contact-dependent and preceded the increase in levels of ERS markers and the activation of the pro-apoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase12, CHOP and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts.
PMID: 22473610 [PubMed - as supplied by publisher]
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