Seizures are a common and life-threatening complication of individuals suffering from infections and inflammation in the central nervous system. In these individuals, seizures develop due to a variety of reasons including breakdown of the blood-brain barrier, changes in ionic homeostasis, and/or increased abundance of inflammatory proteins such as cytokines and antibodies. But, how these changes in the brain alter synaptic wiring and neurotransmission that cause epileptiform activity is largely unknown. The protozoan parasite Toxoplasma gondii infects approximately one-third of the world's population. Most people are asymptomatic because the parasite resides latently within brain and other tissues. But individuals who are immunocompromised or are infected in utero develop toxoplasmosis when the parasite reactivates and the host immune response is unable to control parasite replication or is dysregulated leading immune-mediated tissue destruction. If reactivation occurs in the brain, the resulting toxoplasmic encephalitis presents with a variety of neurological sequelae that includes seizures. Using a murine model for toxoplasmic encephalitis our data indicates that Toxoplasma specifically alters the distribution of key proteins that localie to GABAergic synapses. This change in GABAergic synaptic connectivity causes the mice to develop seizures because these synapses are critical for controlling the flow and timing of information transfer in the brain. This work will define how these proteins are mislocalized (Aim 1), determine the role of inflammatory cells in GABAergic protein mislocalization (Aim 2), and identify the parasite factors that affect GABAergic protein localization and onset of seizures (Aim3). The long-term goal of this work is to determine how seizures develop in Toxoplasma-infected individuals and use this information to generate novel therapies to treat these patients and others suffering from infection-induced seizures.

Public Health Relevance

Toxoplasma gondii is a parasite that causes significant disease in AIDS patients as well as cancer patients and fetuses. These patients suffer from seizures and other neurological complications due to mechanisms that are not known. The goal of this work is to elucidate these mechanisms and use this information to enhance patient outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI124677-03
Application #
9412425
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wali, Tonu M
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
Liang, Chen; Kerr, Alicia; Qiu, Yangfengzhong et al. (2017) Optic Nerve Hypoplasia Is a Pervasive Subcortical Pathology of Visual System in Neonates. Invest Ophthalmol Vis Sci 58:5485-5496
Wohlfert, Elizabeth A; Blader, Ira J; Wilson, Emma H (2017) Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle. Trends Parasitol 33:519-531
Jin, Richard M; Blair, Sarah J; Warunek, Jordan et al. (2017) Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma gondii Infection. J Immunol 198:352-362
Brooks, Justin M; Carrillo, Gabriela L; Su, Jianmin et al. (2015) Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System. MBio 6:e01428-15