Toxoplasma gondii is an obligate intracellular parasite in the phylum Apicomplexa. This parasite causes life-threatening diseases in AIDS patients and immune-compromised individuals, and birth defects or abortions when women are infected during pregnancy. An essential process for pathogenesis and persistence of T. gondii in human hosts is the interconversion between the rapidly dividing tachyzoites and latent bradyzoites. Despite its pathological significance, the signaling molecules and the mechanisms underlying this process are poorly understood. Recently, ubiquitous O-GlcNAcylation and O-GlcNAc transferase (OGT), the enzyme that catalyzes this process, have been identified in T. gondii. OGT adds a single ?-N-acetylglucosamine to serine or threonine residues of intracellular proteins. Because in mammalian organisms, O-GlcNAc is a mediator of intracellular signaling, transcription regulation, and protein trafficking in response to cellular nutrients or stress, we hypothesize that O-GlcNAc may serve as an active player in T. gondii's life cycle transition between tachyzoites and bradyzoites by dynamically modifying intracellular proteins. To test this hypothesis, we will use a chemoenzymatic approach to identify O-GlcNAc-modified proteins in T. gondii tachyzoites (Aim 1). Next, we will apply this approach for comparative analysis of changes in protein O-GlcNAc status in T. gondii tachyzoite-bradyzoites transition. We will focus our studies on gene-regulatory proteins that are involved in this process. Once identified, we will characterize the role of O-GlcNAc in mediating the biological functions of these modified proteins in this life-cycle transition (Aim 2). Finally, we will characterize how changes in global protein O-GlcNAcylation mediated by OGT influence the life-cycle transition of T. gondii (Aim 3).

Public Health Relevance

Toxoplasma gondii is an obligate human pathogen that causes life-threatening diseases in AIDS patients and immune-compromised individuals, and birth defects or abortions when women are infected during pregnancy. Given the critical roles of protein O-GlcNAcylation in eukaryotic signaling, transcription or protein trafficking in response t cellular nutrients or stress, and its abundance in T. gondii, a comprehensive understanding of O-GlcNAcylation in T. gondii will likely provide avenues for the development of new chemotherapeutics to prevent or control infection by this parasite.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI101801-02
Application #
8719923
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
Silmon de Monerri, Natalie C; Kim, Kami (2014) Pathogens hijack the epigenome: a new twist on host-pathogen interactions. Am J Pathol 184:897-911