Toxoplasma gondii is a significant opportunistic infection of HIV/AIDS patients. Reactivated infection during immune suppression in AIDS causes a difficult to treat and life-threatening acute Toxoplasmic encephalitis. No treatment is currently available that can eradicate latent tissue cysts or prevent the risk of reactivated infection in HIV/AIDS patients. Itis essential to identify new strategies and new targets that have the ability to effectively prevent and treat recurrent infections in HIV/AIDS patients. Toxoplasma gondii strain type-dependent virulence mechanisms mediated by rhoptry proteins neutralize key mechanisms of host innate immunity that destroy intracellular parasites. The elucidation of parasite strain type-independent virulence factors could establish new drug targets for both acute and chronic infections caused by different parasite strain types. Dense granule GRA12 gene paralogs are highly conserved between different Toxoplasma strain types. We hypothesize that GRA12 gene paralogs are central regulators of virulence, stage differentiation, cyst biology, and infectivity. In specific im 1 we will use a targeted genetic approach to determine whether dense granule GRA12 gene paralogs are strain type-independent virulence factors. We will also determine whether GRA12 gene paralogs influence, or are associated with, rhoptry protein mediated virulence mechanisms.
In specific aim 2 we will examine the role of GRA12 gene paralogs in cyst stage biology using in vitro and in vivo assays to address their functions in stage differentiation, cyst development, and chronic infection.
This aim will also examine the hypothesis that GRA12 gene paralogs play an essential role in maintaining cyst burdens during chronic infection. Collectively, these aims explore key virulence and pathogenesis mechanisms of protein members of a newly identified GRA12 gene family. Thus, this high impact project will identify GRA12 gene paralogs as new drug targets to intercept acute and chronic phases of infection. This research project explores biology that is novel and carries fundamental importance for successful intracellular parasitism, stage differentiation, and transmission. Consequently, this R21 project holds extremely high innovation as well as the potential for a sustained, powerful impact in the field.

Public Health Relevance

Current treatments for lethal Toxoplasma infections are problematic, and there is no current treatment that can eradicate latent Toxoplasma gondii infection in the ~ 100 million infected individuals residing in the USA. This high impact research project investigates a group of secreted molecules that are required for acute and chronic stages of infection. This project will validate these molecules and their functions as important drug targets for treating and preventing infection and the project is expected to result in improved treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Wali, Tonu M
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Dartmouth College
Schools of Medicine
United States
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Fox, Barbara A; Sanders, Kiah L; Rommereim, Leah M et al. (2016) Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity. PLoS Genet 12:e1006189
Bzik, David J (2016) Serial Dissection of Parasite Gene Families. Infect Immun 84:1252-1254
Rommereim, Leah M; Bellini, Valeria; Fox, Barbara A et al. (2016) Phenotypes Associated with Knockouts of Eight Dense Granule Gene Loci (GRA2-9) in Virulent Toxoplasma gondii. PLoS One 11:e0159306
Leroux, Louis-Philippe; Dasanayake, Dayal; Rommereim, Leah M et al. (2015) Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages. Int J Parasitol 45:319-32
Lopez, Jodie; Bittame, Amina; Massera, CĂ©line et al. (2015) Intravacuolar Membranes Regulate CD8 T Cell Recognition of Membrane-Bound Toxoplasma gondii Protective Antigen. Cell Rep 13:2273-86