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Control of virus-induced lung sequelae by P2RX7-expressing CD4+ T cells

Award Number: R01HL178722
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Control of virus-induced lung sequelae by P2RX7-expressing CD4+ T cells - Project summary: The overarching goal of this project is to define how the damage induced by severe respiratory infections can promote pathogenic lung CD4+ T cells which, in turn, perpetuates the lung sequelae. In response to infections such as influenza or SARS-CoV2, T cells are recruited to the lung parenchyma and establish tissue residency. That includes helper CD4+ T cells, which produce cytokines and support other lung immune responses. In mild infected individuals, lung-resident CD4+ T cells can form protective memory populations, which are important against viral re-exposure. In contrast, severe infections with these viruses can lead to an excessive accumulation of lung-resident CD4+ T cells, which is correlated with the development of widespread lung damage, which is often not reversible. These non-reversible sequelae are typical clinical observations of patients with “Long COVID” and (more recently appreciated) “Long Flu”, i.e., patients with irreversible loss of organ function due to past respiratory viral infections. Understanding how and whether lung pathogenic CD4+ T cell responses form will pave the way for novel strategies to prevent or treat the long-term complications of respiratory viral infections. On this direction, we found, in recently published studies, that lung- resident CD4+ T cells with characteristics of the follicular helper subset (called “tissue-resident helper” or TRH cells) accumulate at excessive numbers in response to severe influenza-infected mice and in COVID-19 patients with lung sequelae. These lung TRH cells express high levels of the receptor P2RX7, a purinergic ion channel that responds to the “danger signal” extracellular ATP (eATP). Notably, our recently published studies also defined that expression of P2RX7 is necessary for the accumulation of lung TRH cells in response to severe influenza, and knockout of this molecule protects mice from long-term lung damage. In this proposal, we aim to define how recognition of eATP through P2RX7 promotes the establishment of pathogenic lung TRH cells, and if P2RX7 blockade can prevent or revert lung sequelae caused by severe respiratory infections. In Aim 1, we will determine how P2RX7/eATP promotes the ability of CD4+ T cells to enter the lung tissue and differentiate into pathogenic TRH cells. We will build upon preliminary data and test the hypothesis that P2RX7 is needed for (a) the induction of CXCR3-mediated CD4+ T cell lung parenchymal infiltration, and (b) their localization into lung dysplastic areas for the conversion into the TRH cell phenotype. To answer these questions, we will use a combination of genetic and pharmacological approaches, as well as a series of ex vivo and in vivo imaging and spatial transcriptomics assessments. In Aim 2, we will test if pharmacological inhibition of P2RX7 can be used to (a) prevent and/or (b) revert the lung sequelae caused by severe influenza or SARS-CoV2. We will build upon preliminary data showing that blockade of this receptor is sufficient to decrease the numbers of lung TRH cells. Our proposed studies will define how eATP regulate lung-resident pathogenic CD4+ T cell responses, and how P2RX7 blockade can be used therapeutically to treat lung disease caused by respiratory viruses.


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 = $1,665,204 )
2026	2026	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Lung Diseases Research	000	1	7/14/2026	NEW	$1,665,204
														Subtotal = $1,665,204

Grand Total All Awards = $1,665,204

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Control of virus-induced lung sequelae by P2RX7-expressing CD4+ T cells

Award Number: R01HL178722

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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