Toxoplasma gondii is a serious pathogen of humans and livestock in the U.S.A. and world-wide. In addition to its well-known disease-causing abilities in the developing fetus, in the past two decades this protozoan parasite has increased its notoriety through the fatal disease it can cause in AIDS patients. Many studies have shown that the disease outcome in animals and probably people is dependent on which strain of the parasite is responsible for the infection. Knowing the basis for these differences is of great clinical importance in allowing the treatment to be matched to the specifics of the infection. For example, some strains may produce the most serious consequences through an excessive immune response rather than through direct tissue destruction by the parasite itself. Conversely, other strains may be so invasive that the immune response can't keep up and so the patient is overwhelmed by the parasite. Treating these two scenarios requires completely different strategies: in one, steroids or other immunosuppressive treatments might be the best choice while in the other, the immune system may need to be helped, not impaired, and rapid treatment with anti-parasite agents is needed. The goal of our work is to understand the molecular basis for strain-specific differences in the host-pathogen interaction. Our approach has been to use a combination of in vitro and in vivo studies to compare different strains and thereby acquire a detailed understanding of the phenomenology behind the different phenotypes. We use genome-wide analysis of how different strains interact with the infected host cell as well as detailed in vivo analysis that follows the exact progression of disease using methods that allow the infection to be monitored in live animals in a non-invasive way. Once these phenotypes are determined, we use crosses between the different strains of Toxoplasma to map the genes involved. Finally, we employ a combination of molecular genetic and cell biological approaches to verify the involvement of the candidate genes and determine the mechanism of their action with special attention to how the different alleles play out as differences in disease-causing properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073756-03
Application #
7656883
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Joy, Deirdre A
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$388,376
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Blank, Matthew L; Parker, Michelle L; Ramaswamy, Raghavendran et al. (2018) A Toxoplasma gondii locus required for the direct manipulation of host mitochondria has maintained multiple ancestral functions. Mol Microbiol 108:519-535
Guiton, Pascale S; Sagawa, Janelle M; Fritz, Heather M et al. (2017) An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-?B-like signature in infected host cells. PLoS One 12:e0173018
Child, Matthew A; Garland, Megan; Foe, Ian et al. (2017) Toxoplasma DJ-1 Regulates Organelle Secretion by a Direct Interaction with Calcium-Dependent Protein Kinase 1. MBio 8:
Kelly, Felice D; Wei, Brian M; Cygan, Alicja M et al. (2017) Toxoplasma gondii MAF1b Binds the Host Cell MIB Complex To Mediate Mitochondrial Association. mSphere 2:
Adomako-Ankomah, Yaw; English, Elizabeth D; Danielson, Jeffrey J et al. (2016) Host Mitochondrial Association Evolved in the Human Parasite Toxoplasma gondii via Neofunctionalization of a Gene Duplicate. Genetics 203:283-98
Lorenzi, Hernan; Khan, Asis; Behnke, Michael S et al. (2016) Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes. Nat Commun 7:10147
Franco, Magdalena; Panas, Michael W; Marino, Nicole D et al. (2016) A Novel Secreted Protein, MYR1, Is Central to Toxoplasma's Manipulation of Host Cells. MBio 7:e02231-15
Coffey, Michael J; Sleebs, Brad E; Uboldi, Alessandro D et al. (2015) An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell. Elife 4:
Murphy, James M; Zhang, Qingwei; Young, Samuel N et al. (2014) A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties. Biochem J 457:323-34
Ewald, Sarah E; Chavarria-Smith, Joseph; Boothroyd, John C (2014) NLRP1 is an inflammasome sensor for Toxoplasma gondii. Infect Immun 82:460-8

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