Thursday, September 18, 2025 9/18/2025

COVID-19 airway inflammation is due to Spike inhibition of CFTR signaling

Award Number: R01HL167048
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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COVID-19 airway inflammation is due to Spike inhibition of CFTR signaling - Abstract Over 860,000 COVID-19 deaths have occurred in the U.S., and more than 5.5 million deaths have occurred world-wide. Consequently, development of effective antiviral drugs that block infectivity and airway inflammation continue to be a global health priority. Inflammation in the COVID-19 airway is due to increased NFκB and Epithelial Sodium channel (ENaC) signaling. Cystic fibrosis (CF), a genetic disease caused by inactivating mutations in the CFTR gene, also has the same proinflammatory NFκB and ENaC signaling phenotype in the airway. Using a differentiated human epithelial lung-on-a-chip platform, we find that ACE2, the receptor protein for the SARS-CoV-2 Spike protein, co-immunoprecipitates with CFTR. Furthermore, exposure of differentiated epithelia to the SARS-COV-2 Spike protein dose-dependently suppresses cyclic AMP-dependent CFTR chloride channel activity and CFTR protein expression. Spike-dependent loss of CFTR also activates TRADD-dependent NFκB signaling and proteolytically activates ENaC. We have also found that Spike-dependent loss of CFTR may be due to failure of endosomal recycling to return apical CFTR to the plasma membrane. Finally, we find that nanoMolar concentrations of cardiac glycoside drugs such as ouabain, digitoxin and digoxin, which competitively inhibit Spike:ACE2 binding, rescue Spike-dependent reduction in CFTR activities. We have therefore hypothesized that binding of SARS-CoV-2 Spike protein to ACE2 in the lung causes loss of CFTR signaling and activation of proinflammatory NFκB and ENaC signaling. To further test this hypothesis we propose the following Specific Aims: SA #1: To define the mechanism by which SARS-CoV-2 Spike protein reduces CFTR channel activity and CFTR protein levels. We will determine the mechanism by which ACE2 interacts with CFTR. We will determine the mechanism by which Spike protein interaction with ACE2 leads to loss of CFTR. SA#2: To define the mechanism by which SARS-CoV-2 Spike protein drives activation of ENaC and NFκB signaling. We will determine the mechanism by which Spike-induced loss of CFTR protein results in activation of TRADD- dependent NFκB ENaC signaling. SA#3: To identify protective mechanisms of cardiac glycosides on cell and animal models of COVID-19 disease. We will test whether cardiac glycoside drugs block native SARS- CoV-2 infection of epithelia and rescue hamster models of COVID-19. . Novelty and Significance: To our knowledge this is the first time COVID-19 airway inflammation has been traced to inhibition of CFTR signaling. Consistently, COVID-19 patients who are also CF carriers, with only one wildtype CFTR gene and only 50% of CFTR function, were recently reported to suffer more severe COVID-19 symptoms and earlier death than normal subjects with COVID-19.


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 = $635,380 )
2025	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Lung Diseases Research	000	3	1/9/2025	NON-COMPETING CONTINUATION	$571,842
2025	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Lung Diseases Research	001	3	8/19/2025	NON-COMPETING CONTINUATION	$63,538
														Subtotal = $635,380

Issue Date FY: 2024 ( Subtotal = $574,708 )
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Lung Diseases Research	001	2	6/14/2024	NON-COMPETING CONTINUATION	$46,916
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Lung Diseases Research	000	2	12/22/2023	NON-COMPETING CONTINUATION	$527,792
														Subtotal = $574,708

Issue Date FY: 2023 ( Subtotal = $663,601 )
2023	2023	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Lung Diseases Research	000	1	1/11/2023	NEW	$573,412
2023	2023	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Lung Diseases Research	001	1	1/23/2023	NEW	$90,189
														Subtotal = $663,601

Grand Total All Awards = $1,873,689

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COVID-19 airway inflammation is due to Spike inhibition of CFTR signaling

Award Number: R01HL167048

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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