Toxoplasma gondii is a serious pathogen of humans and livestock in the U.S.A. and world-wide. In addition to its well-known pathogenesis in the developing fetus, in recent years this protozoan parasite has increased its notoriety through the fatal disease it can cause in AIDS patients. Currently, there is no vaccine for Toxoplasma that is designed to impact human health. As well, the existing drugs are toxic and poorly tolerated in long-term treatment, as is necessary with AIDS patients. There is thus an urgent need for further research in these areas. Disease in AIDS patients is thought to largely result from the reactivation of a chronic infection that persists through the ability of the parasite to differentiate from the actively dividing tachyzoite stage to an encysted bradyzoite stage. In healthy people, the occasional rupture of these cysts is easily dealt with by the immune system but, upon becoming immuno-compromised, such releases result in the dissemination and uncontrolled growth of the virulent tachyzoite form. The resulting tissue destruction, particularly in the brain and lungs can lead to severe disease or even death. The goal of this proposal is to identify the genes involved in differentiation from tachyzoite to bradyzoite and then exploit our findings to engineer a strain that could form the basis for a vaccine in livestock, which represents a major source of human infection. Our approach to identifying the genes is to generate mutants defective in the tachyzoite to bradyzoite differentiation in vitro. The affected genes will be identified by complementation and characterized with regard to their role in the differentiation process. They will then be deleted and the resulting strains examined for their ability to infect and persist in animals. The result will be a strain that is self-limiting and non- transmissible since tachyzoites are not naturally infectious. This could form the appropriate genetic background for further alterations that attenuate virulence to create the ideal vaccine strain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041014-04
Application #
6170019
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Fairfield, Alexandra
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$260,073
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Buchholz, Kerry R; Bowyer, Paul W; Boothroyd, John C (2013) Bradyzoite pseudokinase 1 is crucial for efficient oral infectivity of the Toxoplasma gondii tissue cyst. Eukaryot Cell 12:399-410
Mitra, Rupshi; Sapolsky, Robert Morris; Vyas, Ajai (2013) Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion. Dis Model Mech 6:516-20
Caffaro, Carolina E; Koshy, Anita A; Liu, Li et al. (2013) A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites. PLoS Pathog 9:e1003331
Poukchanski, Anna; Fritz, Heather M; Tonkin, Michelle L et al. (2013) Toxoplasma gondii sporozoites invade host cells using two novel paralogues of RON2 and AMA1. PLoS One 8:e70637
Fritz, Heather M; Buchholz, Kerry R; Chen, Xiucui et al. (2012) Transcriptomic analysis of toxoplasma development reveals many novel functions and structures specific to sporozoites and oocysts. PLoS One 7:e29998
Fritz, Heather M; Bowyer, Paul W; Bogyo, Matthew et al. (2012) Proteomic analysis of fractionated Toxoplasma oocysts reveals clues to their environmental resistance. PLoS One 7:e29955
Koshy, Anita A; Dietrich, Hans K; Christian, David A et al. (2012) Toxoplasma co-opts host cells it does not invade. PLoS Pathog 8:e1002825
Buchholz, Kerry R; Fritz, Heather M; Chen, Xiucui et al. (2011) Identification of tissue cyst wall components by transcriptome analysis of in vivo and in vitro Toxoplasma gondii bradyzoites. Eukaryot Cell 10:1637-47
Dass, Shantala Arundathi Hari; Vasudevan, Anand; Dutta, Deborah et al. (2011) Protozoan parasite Toxoplasma gondii manipulates mate choice in rats by enhancing attractiveness of males. PLoS One 6:e27229
Pernas, Lena; Boothroyd, John C (2010) Association of host mitochondria with the parasitophorous vacuole during Toxoplasma infection is not dependent on rhoptry proteins ROP2/8. Int J Parasitol 40:1367-71

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