The disease that Toxoplasma causes in humans ranges from essentially asymptomatic to debilitating or even fatal. There are likely many reasons for this difference but unambiguous evidence from animal studies and recent data from clinical studies in humans indicate that strain differences in the parasite likely play a major rol. Genetic studies of the parasite have led to the identification of a small number of genes that differ between strains and that interface with the innate immune system in dramatically different ways. The on-going goals of this work are to identify these proteins and determine the molecular basis for their strain-specific effects. In the prior funding period, it was discovered that the recruitment of host mitochondria to the parasitophorous vacuole is a strain-specific phenomenon and the gene responsible for this difference, mitochondrial-association factor 1 or MAF1, was identified.
The first aim of the current proposal is to determine how MAF1 recruits mitochondria, the precise nature of the strain-specific differences in its action and the downstream consequences in terms of interactions with the host. Mitochondria are being increasingly recognized as key to innate immune functions and so these differences are likely to play out in important ways in pathogenesis. Macrophages are key players in some of the earliest immune responses and progress in the first funding period revealed a role for several polymorphic Toxoplasma genes in mediating the response of these cells.
The second aim of the current proposal is to identify the genes responsible for two of these strain-specific differences and determine the molecular basis for the downstream effects that are observed.
Both aims will be accomplished through a combination of molecular genetics, imaging and in vivo studies.

Public Health Relevance

The work described here is relevant to the control of important parasitic diseases such as toxoplasmosis and malaria. Specifically, it will increase our understanding of the mechanisms used by these parasites to co-opt the functions of the human cells they infect. Determining how differences between Toxoplasma strains result in different interactions with their human hosts will help optimize treatment for each patient.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI073756-10
Application #
9096712
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Joy, Deirdre A
Project Start
2007-04-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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:
Grover, Harshita Satija; Chu, H Hamlet; Kelly, Felice D et al. (2014) Impact of regulated secretion on antiparasitic CD8 T cell responses. Cell Rep 7:1716-1728
Shastri, Anjali J; Marino, Nicole D; Franco, Magdalena et al. (2014) GRA25 is a novel virulence factor of Toxoplasma gondii and influences the host immune response. Infect Immun 82:2595-605

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