Infection with the parasite Toxoplasma is of public health importance in the context of maternal-fetal transmission, and is a leading cause of food borne mortality in the US. Approximately 60 million people in this country are chronically infected and reactivation of the latent cyst form of the parasite in patients with defects in T cel function remains a significant cause of morbidity and mortality. As primary infection of immune competent individuals can result in severe disease and T. gondii is easily transmitted, this parasite is a Class B Biodefense pathogen and an NIAID Emerging/Re-emerging Pathogen of concern to human health. Resistance to this parasite in the brain is mediated by CD4+ and CD8+ T cells that produce IFN-?, which activates local cells to control parasite replication. Astrocytes are the most numerous cell populations in the CNS and have been implicated in direct anti-microbial activities as well as coordinating the entry and migration of T cells that respond to infections that affect the brain. The proposed studies focus on the role of the cytokines IFN-? and the type I IFNs in activating astrocytes to control Toxoplasma. Experiments are proposed to identify the pathways downstream of these cytokines that allow human and murine astrocytes to control parasite replication and which coordinate innate and adaptive responses in the CNS. These studies will be complemented by work to understand how a novel nuclear hormone receptor TLX impacts on astrocyte and immune cell function. Together, the approaches proposed will provide new insights into how astrocytes respond to T. gondii, control this pathogen and regulate local effector T cells with the ultimate goal of being able to develop strategies to augment immunity to T. gondii (and other pathogens) within the CNS.

Public Health Relevance

Toxoplasmic encephalitis is a cause of significant morbidity in patients that were infected congenitally or in adults with underlying T cell defects. While there i an interest in using immune therapies to better manage this clinical disease, the underlying T cell defects in these individuals make it unlikely that targeting T cell function alone will prove effective. Therefore, it would be useful to understand how other cell types contribute to the local control of T. gondii and this proposal is focused on understanding how astrocytes contribute to immunity under normal circumstances and should provide new leads to eradicate this parasite.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041158-19
Application #
9638521
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Pesce, John T
Project Start
1996-08-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Glatman Zaretsky, Arielle; Konradt, Christoph; D├ępis, Fabien et al. (2017) T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow. Cell Rep 18:1906-1916
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Konradt, Christoph; Ueno, Norikiyo; Christian, David A et al. (2016) Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system. Nat Microbiol 1:
Konradt, Christoph; Hunter, Christopher A (2015) Immune-mediated viral clearance from the CNS without collateral damage. J Exp Med 212:1141-2
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Dupont, Christopher D; Harms Pritchard, Gretchen; Hidano, Shinya et al. (2015) Flt3 Ligand Is Essential for Survival and Protective Immune Responses during Toxoplasmosis. J Immunol 195:4369-77

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