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Group 1 Metabotropic Glutamate Receptor?s Influence on T Cells During Chronic Toxoplasma Infection

Award Number: F31AI154828
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 09/10/2022

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Group 1 Metabotropic Glutamate Receptor?s Influence on T Cells During Chronic Toxoplasma Infection - PROJECT SUMMARY/ABSTRACT Toxoplasma gondii (T. gondii) is one of the most effective transmissible pathogens in the world, infecting approximately two billion people. Encystment of the parasite in neurons in the brain results in a lifelong chronic infection. Within the brain, a pro-inflammatory response is essential to prevent parasite reactivation. Infection in the immunocompromised leads to lethal toxoplasmic encephalitis while in the immunocompetent, there is persistent low-grade inflammation which lacks clinical symptoms. This suggests that there is a tightly regulated inflammatory response to T. gondii in the brain. T cells are the dominant immune cell that control recrudescence and parasite replication through secretion of effector molecules such as perforins and IFN-γ. However, little is known on how these cells are regulated in this tissue. During chronic infection there is an increase in extracellular (EC) glutamate. High EC glutamate is not specific to T. gondii infection and can occur during multiple pathologies but may be an important environmental signal to tissue specific immune cells. We hypothesize that this glutamate-rich environment plays a role in T cell function and regulation. Preliminarily data demonstrate that T cells from the T. gondii -infected brain express the G-protein coupled metabotropic glutamate receptors (mGluR’s), mGluR1 and mGluR5. This expression is enriched in T cells recruited to the brain compared to secondary lymphoid derived cells. This project aims to: 1) define group 1 mGluR expressing T cells in the brain during infection, and determine if there is a functional difference compared to the periphery. This will be done by characterizing surface proteins for canonical T cell subsets, testing the secretion of effector molecules, defining if they localize to distinct regions of the brain, and characterizing the transcriptional profile at a single cell level; 2) determine how group 1 mGluR’s regulate T cells in response to infection. This will be done by tracking adoptively transferred mGluR-deficient T cells in an infected wild type recipient, and by activating or inhibiting these receptors ex vivo, followed by measuring changes in viability, proliferation, cytokine production, and canonical Gq molecules; 3) determine if lowering the glutamate concentrations in the infected brain will alter the T cell recruitment profile to the central nervous system (CNS). This will be done by characterizing mGluR expressing T cells recruited to the brain after ceftriaxone treatment, an antibiotic previously used in our lab to lower exogenous glutamate in the brain by increasing glutamate transporter-1 expression. Overall, this proposal will help us understand how tissue- derived signals influence protective immunity. Furthermore, what we learn from our proposed studies could be broaden to other fields such as neurodegenerative research, as some of these neurological maladies not only have a commonality of glutamate alteration, but also a recruitment of T cells to the CNS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$38,276 )
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	000	2	12/15/2022	NON-COMPETING CONTINUATION	-$27,835
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	001	2	7/21/2023	NON-COMPETING CONTINUATION	-$10,441
														Subtotal = -$38,276

Issue Date FY: 2022 ( Subtotal = $38,994 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	000	2	8/19/2022	NON-COMPETING CONTINUATION	$38,994
														Subtotal = $38,994

Issue Date FY: 2021 ( Subtotal = $38,037 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	000	1	7/16/2021	NEW	$38,037
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Allergy and Infectious Diseases Research	001	1	7/16/2021	NEW	$0
														Subtotal = $38,037

Grand Total All Awards = $38,755

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Group 1 Metabotropic Glutamate Receptor?s Influence on T Cells During Chronic Toxoplasma Infection

Award Number: F31AI154828

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 09/10/2022

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