Reactivation of dormant Toxoplasma gondii bradyzoite cysts in the central nervous system in AIDS patients causes Toxoplasmosis, a dangerous and difficult to treat recurrent encephalitis. No treatments are currently available for AIDS patients to eliminate the dormant Toxoplasma bradyzoite cysts, to prevent their reactivation, or to prevent the development of new cysts after reactivated disease occurs. The absence of any current curative or preventative treatment for AIDS patients to reduce the risk of disease associated with Toxoplasma infection is due primarily to a major gap in basic knowledge regarding the fundamental parasite biology of chronic infection. Several Toxoplasma rhoptry secreted (ROP) protein virulence factors are crucial for parasite survival during acute infection and enable parasite survival necessary to establish the chronic stages of infection defined by bradyzoite cysts. Our recent findings identified novel rhoptry proteins encoded by the ROP38 locus that while essential for the chronic bradyzoite cyst stages are not necessary for the acute stages of infection or parasite virulence. Consequently, investigation of the ROP38 locus enables a specific analysis of mechanisms that influence cyst burdens in chronic infection. The ROP38 locus contains 6 genes that encode ROP proteins with signatures of active kinases (ROPKs). In this exploratory R21 project we will examine aspects of host - parasite interaction and mechanisms associated with the ROP38 locus that are crucial for chronic stages of infection. This is a novel area of biological investigation because the existence of ROPKs that control chronic infection but not acute infection were previously unknown. Through the investigation of the biological functions of the ROP38 locus, this high risk - high impact exploratory R21 study has the potential to reveal new aspects of parasite biology.

Public Health Relevance

Reactivation of dormant Toxoplasma gondii bradyzoite cysts in the central nervous system in AIDS patients causes Toxoplasmosis, a dangerous and difficult to treat recurrent encephalitis. The absence of any current curative or preventative treatment for AIDS patients to reduce the risk of disease associated with Toxoplasma infection is due primarily to a major gap in basic knowledge regarding fundamental parasite biology of chronic infection. By examining fundamental parasite mechanisms associated with the ROP38 locus that are crucial for chronic stages of infection, we expect to identify biology that can inform new strategies to target the chronic stages of this parasite.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI129869-02
Application #
9393301
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2016-12-05
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Fox, Barbara A; Butler, Kiah L; Guevara, Rebekah B et al. (2017) Cancer therapy in a microbial bottle: Uncorking the novel biology of the protozoan Toxoplasma gondii. PLoS Pathog 13:e1006523