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Structural Basis for T Cell Recognition of SARS-CoV-2

Award Number: R21AI169181
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Structural Basis for T Cell Recognition of SARS-CoV-2 - Project Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Elucidating the mechanisms underlying the adaptive immune response to SARS-CoV-2 is crucial for predicting vaccine efficacy and assessing the risk of reinfection. Neutralizing antibodies against SARS-CoV-2 have been studied extensively and are clearly protective, but may be short-lived and are not elicited in all infected individuals. Mounting evidence indicates that T cells play a vital role in the clearance of SARS-CoV-2 and in formation of long-term memory responses to this virus. Extensive structural information is now available on neutralizing antibodies from COVID-19 convalescent patients (CPs) bound to the SARS-CoV-2 spike trimer or RBD (>330 PDB entries), resulting in a comprehensive picture of the B cell response to this virus. By contrast, very little structural information is available for SARS-CoV-2-specific TCRs bound to their peptide–MHC (pMHC) targets (4 PDB entries), despite the increasingly appreciated role of T cell-mediated immunity in combatting COVID-19. Our goal is to address this major unmet need by obtaining atomic-level information on SARS-CoV-2 recognition by MHC class I-restricted TCRs from COVID-19 CPs. We will focus on CD8+ T cell epitopes because cytotoxic CD8+ T cells participate directly in viral clearance. Our Specific Aims are: Aim 1: Determine crystal structures of TCR–pMHC complexes. We will target for X-ray crystallographic analysis TCRs specific for epitopes that elicit high levels of TCR expansion in COVID-19 CPs, as well as TCRs associated with protection. To demonstrate feasibility, we have already determined structures of a public and a private TCR from COVID-19 CPs in complex with HLA-A2 and two SARS-CoV-2 spike (S) epitopes, YLQ and RLQ. We will extend these studies to three additional S epitopes (FVF, FQF, RLN) and three nucleocapsid (N) epitopes (LLL, LQL, SPR), which elicit strong T cell responses, and are presented by HLA-A2 or HLA-B7 MHCs. We have diverse panels of TCRs targeting each of these CD8+ T cell epitopes. Aim 2: Analysis of TCR–pMHC structures. TCR–pMHC complex structures determined in Aim 1 will be analyzed using advanced computational structural biology tools to delineate key features of their recognition, as well as the predicted targeting of epitope variants from SARS-CoV-2 and related coronaviruses. These studies will yield foundational knowledge about TCR recognition of SARS-CoV-2 epitopes, about the generation of clonal diversity in epitope-specific TCR repertoires, and about the ways mutations in these epitopes may enable the virus to escape immune surveillance.


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: 2026 ( Subtotal = $0 )
2026	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	2/11/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $193,671 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	7/29/2024	NON-COMPETING CONTINUATION	$193,671
														Subtotal = $193,671

Issue Date FY: 2023 ( Subtotal = $232,710 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	8/3/2023	NEW	$232,710
														Subtotal = $232,710

Grand Total All Awards = $426,381

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Structural Basis for T Cell Recognition of SARS-CoV-2

Award Number: R21AI169181

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/03/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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