Toxoplasma is an obligate intracellular parasite that can cause serious disease in immunocompromised patients and in the developing fetus. The majority of Toxoplasma isolates from human patients and livestock in Europe and North-America belong to one of three genetically distinct strains, the type I, type II and type III strains. In mice, these three distinct strains differ enormously in virulence and other phenotypes and there is good evidence that in humans this is also the case. Understanding how these distinct Toxoplasma strains differ in causing disease has important clinical implications;some strains may cause disease through over-stimulation of the immune response leading to toxic levels of cytokines while other strains may cause disease mainly through tissue damage caused by the large numbers of parasites present. If it was known how distinct Toxoplasma strains cause disease and with what strain a patient was infected the treatment could be matched to the specifics of the infection;in some cases inhibition of the immune response might be the best choice while in other cases aggressive treatment with anti-parasitic agents might be needed. Our hypothesis is that, besides host and environmental factors, the genotype of the Toxoplasma strain plays a major role in determining disease outcome through differences between strains in modulating host cell signaling pathways. The goal of this grant is therefore the identification and characterization of Toxoplasma gene products involved in strain-specific modulation of host cell signaling pathways. We will first determine differences between virulent and avirulent strains of Toxoplasma in modulating signaling pathways in mouse innate immune cells in vivo. We will then use existing F1 progeny from crosses between these strains to map the Toxoplasma genomic regions involved. Subsequently, we will use molecular genetic approached to identify the Toxoplasma genes involved. Finally, we will characterize the mechanism of action of these genes. The ability to co-opt host signaling pathways for the parasite's own purposes is likely to be found in other Apicomplexa that are also living within a membrane-limited vacuole, for example, Plasmodium species as they grow within hepatocytes. It is therefore expected that a thorough understanding of the mechanisms Toxoplasma uses to modulate host cell signaling will lead to better therapies against this and other Apicomplexan parasites.

Public Health Relevance

Toxoplasma is an obligate intracellular parasite that can cause serious disease in immunocompromised patients and in the developing fetus. It is expected that the results of this grant will lead to a thorough understanding of the mechanisms Toxoplasma uses to modulate host cell signaling. This could lead to better therapies against this and other Apicomplexan parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080621-04
Application #
8291223
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2009-07-10
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$404,403
Indirect Cost
$159,378
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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
Sidik, Saima M; Huet, Diego; Ganesan, Suresh M et al. (2016) A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes. Cell 166:1423-1435.e12
Fink, Avner; Hassan, Musa A; Okan, Nihal A et al. (2016) Early Interactions of Murine Macrophages with Francisella tularensis Map to Mouse Chromosome 19. MBio 7:e02243
Jensen, Kirk D C; Camejo, Ana; Melo, Mariane B et al. (2015) Toxoplasma gondii superinfection and virulence during secondary infection correlate with the exact ROP5/ROP18 allelic combination. MBio 6:e02280
Hassan, Musa A; Jensen, Kirk D; Butty, Vincent et al. (2015) Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection. PLoS Genet 11:e1005619
Gold, Daniel A; Kaplan, Aaron D; Lis, Agnieszka et al. (2015) The Toxoplasma Dense Granule Proteins GRA17 and GRA23 Mediate the Movement of Small Molecules between the Host and the Parasitophorous Vacuole. Cell Host Microbe 17:642-52
Gorfu, Gezahegn; Cirelli, Kimberly M; Melo, Mariane B et al. (2014) Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii. MBio 5:
Camejo, Ana; Gold, Daniel A; Lu, Diana et al. (2014) Identification of three novel Toxoplasma gondii rhoptry proteins. Int J Parasitol 44:147-60
Cannella, Dominique; Brenier-Pinchart, Marie-Pierre; Braun, Laurence et al. (2014) miR-146a and miR-155 delineate a MicroRNA fingerprint associated with Toxoplasma persistence in the host brain. Cell Rep 6:928-37
Hassan, Musa A; Saeij, Jeroen P J (2014) Incorporating alternative splicing and mRNA editing into the genetic analysis of complex traits. Bioessays 36:1032-40

Showing the most recent 10 out of 30 publications