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The generation and protective function of lung tissue resident memory T cells following SARS-CoV-2 infection or vaccination

Award Number: R01AI167372
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The generation and protective function of lung tissue resident memory T cells following SARS-CoV-2 infection or vaccination - Project Summary/Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), has exploded into a global pandemic causing significant loss of life, pronounced economic impact and significant long-term medical impacts which are still being characterized. Despite impressive protection afforded by the current SARS-CoV-2 vaccines which are primarily mediated by antibody neutralization of virus, these antibodies wane over time and new viral variants have emerged that are less susceptible toby these antibodies. A major question is whether memory T cells afford more long-lasting protection during SARS-CoV-2 infection. Prior studies showed that people who recovered from SARS-CoV infection from 2003 exhibited SARS-CoV- specific memory CD8+ T cell responses in peripheral blood for up to 11 years, virus-specific antibodies were not detectable at 6 years, and there was no cross-reactivity with MERS-CoV peptide1,2. For the current pandemic, we are starting to learn what types of memory T and B cells form after SARS-Cov2 infection in the blood, however we have no idea the longevity of these responses. More importantly, we know very little about the pulmonary memory T and B cells that form in the lung after SARS-CoV-2 infection and, based on what has been learned from other viruses, these may be the most protective memory cells needed for superior long- term immunity to reinfection. In this collaborative proposal between the Teijaro, Kaech and Farber labs, we bring together world- class expertise in anti-viral immunity and lung pathogenesis, immunological memory and human immunology to study the development and protective role of lung-resident TRM cells in SARS-CoV-2. In Aim 1, we will study the fundamentals of SARS-CoV-2 TRM development in the lungs of hACE2-transgenic mice and determine whether TRM are required for long- term immunity, through genetic perturbations of Tgfbr2 and Smad4 in T cells, which are differentially required for TRM differentiation3, and the depletion of circulating memory cells. In Aim 2, we will examine if lung TRM cells contribute to the protection afforded by mRNA vaccines to better understand the role, if any, of memory T cells in mediating protection to SARS-CoV-2 and notable variants of concern (VOC). Lastly, in Aim 3, we extend and complement our studies in mice to Dr. Farber’s human donor repository to assess human memory formation following SARS-CoV-2 infection and vaccination. We hope to answer the basic question of which types of memory T cells form after SARS- CoV-2 infection and confer long-term protective immunity to this virus and VOCs. These studies will provide critical information related to the quality of immunological memory that forms after SARS-CoV- 2 infection in mice and humans and will serve to guide current and future vaccine development.


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: 2025 ( Subtotal = $863,551 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	2/24/2025	NON-COMPETING CONTINUATION	$863,551
														Subtotal = $863,551

Issue Date FY: 2024 ( Subtotal = $884,886 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	3	7/11/2024	NON-COMPETING CONTINUATION	$0
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$88,489
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	2/22/2024	NON-COMPETING CONTINUATION	$796,397
														Subtotal = $884,886

Issue Date FY: 2023 ( Subtotal = $878,617 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	2/3/2023	NON-COMPETING CONTINUATION	$878,617
														Subtotal = $878,617

Issue Date FY: 2022 ( Subtotal = $916,382 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	2/28/2022	NEW	$916,382
														Subtotal = $916,382

Grand Total All Awards = $3,543,436

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The generation and protective function of lung tissue resident memory T cells following SARS-CoV-2 infection or vaccination

Award Number: R01AI167372

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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