TOXOPLASMA ENCEPHALITIS IN AIDS: BRADYZOITE REGULATION

Summary

Principal Investigator: Louis Weiss
Abstract: Toxoplasma gondii is a ubiquitous Apicomplexan protozoan parasite of mammals and birds. It has long been recognized as an important opportunistic pathogen of immune compromised hosts and emerged as a major opportunistic pathogen of the Acquired Immunodeficiency Syndrome (AIDS) epidemic. The predilection of this parasite for the central nervous system (CNS) causing necrotizing encephalitis constitutes its major threat to patients with AIDS. In immune compromised patients, such as those with AIDS, it is believed that CNS toxoplasmosis is due to the reactivation of a chronic or latent infection with tissue cysts (bradyzoites) of T. gondii. In prior studies we have established that bradyzoites within tissue cysts express unique proteins that facilitate their survival. The cyst wall is a critical structure for the survival, reactivation and oral transmission of T. gondii. The widespread distribution of T. gondii in humans and other animals is due to the ability of tissue cysts to permit oral transmission of this infection. In the present proposal, studies will be focused on the characterization of the components of the cyst wall. This will included further characterization of CST1 (a glycoprotein that binds DBA), which we had previously identified as being a cyst wall component that is expressed rapidly during the differentiation process. The components of the cyst wall will be characterized using a combination of proteomic, immunologic and genetic approaches taking advantage of techniques we have developed for purification of the T. gondii cyst wall. These studies will both elucidate the composition of this structure and provide reagents that should prove useful for further studies of the biology and organization of the cyst wall. Defining the structure of the cyst wall is clearly a critical step for understanding the biology of Toxoplasma gondii and should provide valuable information for the development of new strategies for the prevention of reactivation toxoplasmosis.
Funding Period: 1996-04-01 - 2011-01-31
more information: NIH RePORT

Top Publications

  1. pmc Cyclic nucleotide kinases and tachyzoite-bradyzoite transition in Toxoplasma gondii
    Michael S Eaton
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Int J Parasitol 36:107-14. 2006
  2. pmc The Toxoplasma gondii cyst wall protein CST1 is critical for cyst wall integrity and promotes bradyzoite persistence
    Tadakimi Tomita
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America
    PLoS Pathog 9:e1003823. 2013
  3. pmc 3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication
    Yubao Wang
    Department of Pathology, Albert Einstein College of Medicine, Golding 704, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    Mol Biochem Parasitol 173:142-53. 2010
  4. pmc Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria
    Minxian Dai
    Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St Johns University, Queens, NY 11439, USA
    Microbes Infect 12:1198-207. 2010
  5. pmc Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade
    Rajarshi Bhadra
    Department of Microbiology, George Washington University, Washington, DC 20037, USA
    Proc Natl Acad Sci U S A 108:9196-201. 2011
  6. pmc Host Cell Preference of Toxoplasma gondii Cysts in Murine Brain: A Confocal Study
    T C Melzer
    Department of Microbiology, Montana State University, Bozeman, MT 59717, USA
    J Neuroparasitology 1:. 2010
  7. pmc Guidelines for the naming of genes, gene products, and mutants in the opportunistic protists
    Andrew H Limper
    Thoracic Diseases Research Unit, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Eukaryot Microbiol 58:537-8. 2011
  8. pmc Lysine post-translational modifications and the cytoskeleton
    Wendy D Zencheck
    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, U S A
    Essays Biochem 52:135-45. 2012
  9. pmc The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative
    Minxian Dai
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States
    Life Sci 91:687-92. 2012
  10. pmc Altered regulation of Akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment
    Minxian Dai
    Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John s University, Queens, New York, USA
    PLoS ONE 7:e44117. 2012

Scientific Experts

  • Louis Weiss
  • James G Farmar
  • Maria Gulinello
  • Funing Yan
  • Kami Kim
  • Fabiana S Machado
  • Yubao Wang
  • Tadakimi Tomita
  • Amos Orlofsky
  • Minxian Dai
  • Barbara A Fox
  • Sandra E Reznik
  • Herbert B Tanowitz
  • Hui Xiao
  • Tatsuya Yamada
  • Fa Yun Che
  • Andras Fiser
  • Ruth Hogue Angeletti
  • Imtiaz A Khan
  • Brandi Freeman
  • David J Bzik
  • Wendy D Zencheck
  • Yan Fen Ma
  • Henry J Shikani
  • Mahalia S Desruisseaux
  • Andrew H Limper
  • Rajendra Upadhya
  • Jason P Gigley
  • Huan Huang
  • Rajarshi Bhadra
  • Hongshan Zhang
  • Berta Burd
  • T C Melzer
  • Edward Nieves
  • S K Halonen
  • T Melzer
  • Joseph M Dybas
  • T Evering
  • Michael S Eaton
  • Sunder P Shrestha
  • Sandra K Halonen
  • Lye Meng Markillie
  • Ronald C Taylor
  • Rolando Macias
  • Mahalia Sabrina Desruisseaux
  • David Conover Spray
  • Peter Davies
  • Ralph A Stephani
  • J Elias Collado
  • Fernando P Bruno
  • Fernando Pereira Bruno
  • HERBERT BERNARD TANOWITZ
  • Carlos Madrid-Aliste
  • Leah M Rommereim
  • Marie France Cesbron-Delauw
  • Yi Bao
  • RUTH HOGUE-ANGELETTI
  • Corinne Mercier
  • Michael P Lisanti
  • Hattie Lee
  • Alejandra Falla
  • H J Cranston
  • Pascal Verdier-Pinard
  • David C Spray
  • Marilyn Parsons
  • Anuradha Karnataki
  • Kamal El Bissati
  • Joseph F Urban
  • Dmitry Rykunov
  • Carlos J Madrid-Aliste
  • Peter Sayles
  • A Duffy
  • Karen Eberle
  • Rubeena Hakak
  • Tyson Woods
  • Kate McInnerney

Detail Information

Publications39

  1. pmc Cyclic nucleotide kinases and tachyzoite-bradyzoite transition in Toxoplasma gondii
    Michael S Eaton
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Int J Parasitol 36:107-14. 2006
    ..The beta-GAL/CAT reporter parasite provides a method to quantify and compare agents that cause differentiation in T. gondii...
  2. pmc The Toxoplasma gondii cyst wall protein CST1 is critical for cyst wall integrity and promotes bradyzoite persistence
    Tadakimi Tomita
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America
    PLoS Pathog 9:e1003823. 2013
    ..These results indicate that CST1 functions as a key structural component that confers essential sturdiness to the T. gondii tissue cyst critical for persistence of bradyzoite forms. ..
  3. pmc 3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication
    Yubao Wang
    Department of Pathology, Albert Einstein College of Medicine, Golding 704, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    Mol Biochem Parasitol 173:142-53. 2010
    ..Elucidation of the mechanism of 3-MA inhibition may provide insight into the control of parasite growth...
  4. pmc Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria
    Minxian Dai
    Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St Johns University, Queens, NY 11439, USA
    Microbes Infect 12:1198-207. 2010
    ..Thus, cognitive tests similar to those used in these mouse studies could facilitate the development of adjunctive therapies that can ameliorate adverse neurological outcomes in human cerebral malaria...
  5. pmc Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade
    Rajarshi Bhadra
    Department of Microbiology, George Washington University, Washington, DC 20037, USA
    Proc Natl Acad Sci U S A 108:9196-201. 2011
    ..To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8(+) T-cell dysfunction and parasite reactivation...
  6. pmc Host Cell Preference of Toxoplasma gondii Cysts in Murine Brain: A Confocal Study
    T C Melzer
    Department of Microbiology, Montana State University, Bozeman, MT 59717, USA
    J Neuroparasitology 1:. 2010
    ..No cysts were identified in astrocytes, using the astrocyte marker, GFAP. Astrocyte interactions with neuronal-cysts, however, were frequently observed...
  7. pmc Guidelines for the naming of genes, gene products, and mutants in the opportunistic protists
    Andrew H Limper
    Thoracic Diseases Research Unit, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Eukaryot Microbiol 58:537-8. 2011
    ..The following summary reports the consensus agreement to move toward a unified nomenclature system for these organisms. The system is adapted from that used for Saccharomyces cerevisiae...
  8. pmc Lysine post-translational modifications and the cytoskeleton
    Wendy D Zencheck
    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, U S A
    Essays Biochem 52:135-45. 2012
    ..We also review additional lysine modifications, such as ubiquitination and SUMOylation, and their role in protein regulation and processing...
  9. pmc The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative
    Minxian Dai
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States
    Life Sci 91:687-92. 2012
    ....
  10. pmc Altered regulation of Akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment
    Minxian Dai
    Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John s University, Queens, New York, USA
    PLoS ONE 7:e44117. 2012
    ..Aberrant regulation of Akt/GSK3β signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM...
  11. pmc Nonprotein based enrichment method to analyze peptide cross-linking in protein complexes
    Funing Yan
    Department of Biochemistry, and Biodefense Proteomics Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Anal Chem 81:7149-59. 2009
    ..These features may make the method suitable to investigate protein-protein interactions in biological samples...
  12. pmc Microarray analysis of IFN-gamma response genes in astrocytes
    Sandra K Halonen
    Department of Microbiology, Montana State University, Bozeman, 59717, USA
    J Neuroimmunol 175:19-30. 2006
    ....
  13. pmc The immunology of parasite infections in immunocompromised hosts
    T Evering
    Department of Medicine Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Parasite Immunol 28:549-65. 2006
    ..This review does not address the literature on parasitic infections in the setting of HIV-1 infection...
  14. pmc Coinfection with Heligmosomoides polygyrus fails to establish CD8+ T-cell immunity against Toxoplasma gondii
    Imtiaz A Khan
    Department of Microbiology and Tropical Medicine and Immunology, George Washington University, Washington, DC 20037, USA
    Infect Immun 76:1305-13. 2008
    ....
  15. pmc Computational analysis and experimental validation of gene predictions in Toxoplasma gondii
    Joseph M Dybas
    Biodefense Proteomics Research Center, Albert Einstein College of Medicine, Bronx, New York, United States of America
    PLoS ONE 3:e3899. 2008
    ..An essential step towards understanding molecular mechanisms controlling transitions between the various life stages and identifying candidate drug targets is to accurately characterize the T. gondii proteome...
  16. pmc Coordinate control of host centrosome position, organelle distribution, and migratory response by Toxoplasma gondii via host mTORC2
    Yubao Wang
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Biol Chem 285:15611-8. 2010
    ....
  17. pmc Improved techniques for endogenous epitope tagging and gene deletion in Toxoplasma gondii
    Rajendra Upadhya
    Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Microbiol Methods 85:103-13. 2011
    ..gondii UPRT gene locus as a test case. The methods described in this paper represent an improved strategy for efficient epitope tagging and gene disruptions in T. gondii...
  18. pmc Type II Toxoplasma gondii KU80 knockout strains enable functional analysis of genes required for cyst development and latent infection
    Barbara A Fox
    Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Dr, Lebanon, NH 03756, USA
    Eukaryot Cell 10:1193-206. 2011
    ....
  19. pmc Photo-assisted peptide enrichment in protein complex cross-linking analysis of a model homodimeric protein using mass spectrometry
    Funing Yan
    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Proteomics 11:4109-15. 2011
    ..These technical improvements allow this method to be used for investigating protein-protein interactions in complex biological samples...
  20. pmc Molecular cloning and characterization of mitogen-activated protein kinase 2 in Toxoplasma gondii
    Huan Huang
    Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
    Cell Cycle 10:3519-26. 2011
    ..gondii. Since TgMAPK2 is significantly different from its mammalian counterpart, it may be useful as a drug target. This work establishes a foundation for further study for this unique kinase...
  21. pmc Recent developments in the interactions between caveolin and pathogens
    Fabiana S Machado
    Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
    Adv Exp Med Biol 729:65-82. 2012
    ..Trypanosoma cruzi and Toxoplasma gondii. This is a continuing area of research and the final chapter has not been written on this topic...
  22. pmc Toxoplasma gondii inhibits granzyme B-mediated apoptosis by the inhibition of granzyme B function in host cells
    Tatsuya Yamada
    Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Int J Parasitol 41:595-607. 2011
    ..We believe these findings represent the first demonstration of granzyme B inhibition by a cellular pathogen and indicate a new modality for host cell protection by T. gondii that may contribute to parasite immune evasion...
  23. pmc Comprehensive proteomic analysis of membrane proteins in Toxoplasma gondii
    Fa Yun Che
    Department of Pathology, Biodefense Proteomics Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Mol Cell Proteomics 10:M110.000745. 2011
    ..gondii or to the Apicomplexa, providing a set of gene predictions ripe for experimental investigation, and potentially suitable targets for the development of therapeutic strategies...
  24. pmc Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology
    Maria Gulinello
    Behavioral Core Facility, Department of Neuroscience, 1410 Pelham Pkwy S K925, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Microbes Infect 12:528-37. 2010
    ..Such changes point out the subtle interaction of this parasite with its intermediate hosts and are consistent with ideas about increased predation being an outcome of infection...
  25. pmc Post-translational modifications to Toxoplasma gondii alpha- and beta-tubulins include novel C-terminal methylation
    Hui Xiao
    Departments of Pathology, Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Proteome Res 9:359-72. 2010
    ..Methylation, a PTM not previously described on tubulin, was also detected. Methylated tubulins were not detected in the host cells, human foreskin fibroblasts, suggesting that this may be a modification specific to the Apicomplexa...
  26. pmc Toxoplasmosis: A history of clinical observations
    Louis M Weiss
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Int J Parasitol 39:895-901. 2009
    ..gondii as a cause of human disease. This review examines the clinical manifestations of infection with T. gondii and the history of the discovery of these manifestations...
  27. pmc IVICAT for the masses: an improved technique for permethylation of peptides
    James G Farmar
    Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Biomol Tech 20:285-92. 2009
    ..We have modified this technique to be used with standard laboratory equipment so that this chemistry is accessible to most proteomics laboratories...
  28. pmc Proliferation of Toxoplasma gondii in inflammatory macrophages in vivo is associated with diminished oxygen radical production in the host cell
    Sunder P Shrestha
    Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, G704, Bronx, NY 10461, USA
    Int J Parasitol 36:433-41. 2006
    ..ROS function and parasite evasion of this function may contribute significantly to the balance between host defense and disease progression during acute infection...
  29. pmc Intracellular parasitism with Toxoplasma gondii stimulates mammalian-target-of-rapamycin-dependent host cell growth despite impaired signalling to S6K1 and 4E-BP1
    Yubao Wang
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Cell Microbiol 11:983-1000. 2009
    ..The Toxoplasma-infected cell provides a unique example of non-canonical mTOR activation supporting growth that is independent of signalling through either S6K1 or 4E-BP1...
  30. pmc Externally triggered egress is the major fate of Toxoplasma gondii during acute infection
    Tadakimi Tomita
    Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Immunol 183:6667-80. 2009
    ..ETE represents a novel example of interaction between a parasite infectious cycle and host microenvironment...
  31. pmc Toxoplasma: the next 100years
    Kami Kim
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Microbes Infect 10:978-84. 2008
    ..This review addresses recent advances in our understanding of the developmental biology and host-pathogen relationships of T. gondii...
  32. pmc The gamma interferon (IFN-gamma)-inducible GTP-binding protein IGTP is necessary for toxoplasma vacuolar disruption and induces parasite egression in IFN-gamma-stimulated astrocytes
    T Melzer
    Dept of Microbiology, Montana State University, Bozeman, MT 59717, USA
    Infect Immun 76:4883-94. 2008
    ..Fusion of the ER with the PV, releasing calcium into the vacuole, may also be the mechanism by which intravacuolar parasite movement and IFN-gamma-induced parasite egression occur...
  33. pmc Host cell autophagy is induced by Toxoplasma gondii and contributes to parasite growth
    Yubao Wang
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Biol Chem 284:1694-701. 2009
    ..These findings indicate a new role for autophagy as a pathway by which parasites may effectively compete with the host cell for limiting anabolic resources...
  34. pmc Toxoplasma gondii proteomics
    Louis M Weiss
    Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer 504, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    Expert Rev Proteomics 6:303-13. 2009
    ..Web-based resources, such as EPIC-DB and ToxoDB, provide proteomic data and support for studies on T. gondii. This review will summarize the current status of proteomic research on T. gondii...