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Role of ERK1/2 signaling in SARS-CoV-2 -induced dysregulated immunity and lung pathology.

Award Number: R01HL165423
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/06/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Role of ERK1/2 signaling in SARS-CoV-2 -induced dysregulated immunity and lung pathology. - Project Summary (Abstract): Emerging and re-emerging respiratory viruses such as SARS-CoV, MERS-CoV, SARS-CoV-2, and avian and swine influenza viruses continue to pose a significant challenge to public health. These highly pathogenic viruses successfully evade host immunity and replicate to high titers, causing excessive inflammation, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and fatal pneumonia. However, the host and virus factors that facilitate impaired antiviral response and excessive inflammation (dysregulated immunity) that lead to ALI and lung pathology are not known. In novel preliminary findings, we identify that toll-like receptor (TLR)-extracellular regulated kinase (ERK)1/2 activity is central to SARS- CoV-2 and viral-RNA-induced dysregulated lung immunity. Notably, blocking ERK1/2 activity not only reduced SARS-CoV-2-induced inflammatory cytokine production but also enhanced antiviral IFN-I response. Therefore, based on our strong preliminary data, we hypothesize that myeloid cell-intrinsic TLR- ERK1/2 signaling promotes pathogenic lung inflammation and suppresses antiviral immunity. The primary objective of the proposed study is to demonstrate the critical role of myeloid-cell TLR-ERK1/2 signaling in SARS-CoV-2-induced dysregulated immunity, acute lung injury (ALI), and lung pathology, and to evaluate the therapeutic potential of blocking ERK1/2 activity in suppressing lethal inflammation while enhancing antiviral. We will define the role of myeloid cell-intrinsic TLR-ERK1/2 activity in SARS-CoV-2-induced lung injury and pathology (Aim 1), demonstrate the role of myeloid cell intrinsic TLR-ERK1/2 activation in the dysregulation of SARS-CoV-2-specific lung T cell response (Aim 2), and test the therapeutic potential of blocking ERK1/2 signaling with or without antivirals in reducing lung injury and protecting mice from lethal SARS-CoV-2 infection (Aim 3). The results obtained from this study will provide a foundation for identifying specific targets to moderate lung inflammation and injury, which in combination with antivirals, can be used to improve ALI, ARDS, and clinical outcomes.


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 = $487,311 )
2026	2026	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Lung Diseases Research	000	3	7/8/2026	NON-COMPETING CONTINUATION	$487,311
														Subtotal = $487,311

Issue Date FY: 2025 ( Subtotal = $521,972 )
2025	2025	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Lung Diseases Research	000	2	7/23/2025	NON-COMPETING CONTINUATION	$521,972
														Subtotal = $521,972

Issue Date FY: 2024 ( Subtotal = $408,606 )
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Lung Diseases Research	000	1	9/6/2024	NEW	$408,606
														Subtotal = $408,606

Grand Total All Awards = $1,417,889

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Role of ERK1/2 signaling in SARS-CoV-2 -induced dysregulated immunity and lung pathology.

Award Number: R01HL165423

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/06/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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