Thursday, November 21, 2024 11/21/2024

ETS-family Transcription Factor Mediated Control of Pulmonary Inflammation Induced by Influenza Viruses

Award Number: R01AI137031
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Influenza viruses induce significant morbidity and mortality in the human population every year. Despite the medical importance of influenza disease, the mechanisms underlying the viral pathogenesis are incompletely understood. After influenza viruses initiate infection, cellular pattern recognition receptors detect components of the virus and inflammatory cytokines such as type I interferon (IFN) are produced. While an important part of early control of viral replication and spread, excessive or prolonged IFN signaling is associated with immunopathology and more severe viral disease. We have previously shown that some respiratory epithelial cells can survive direct viral infection, display prolonged IFN signaling, and contribute to lung immunopathology likely by delaying epithelial regeneration. Thus, understanding how type I IFN is downregulated represents a critical aspect of influenza disease pathogenesis. Interestingly, however, we failed to detect a difference in any of the canonical IFN induction or suppression pathways in the cells that survived direct viral infection. We therefore hypothesized that there must be additional regulators of IFN signaling relevant for IFN control during the resolution of influenza virus-induced disease. By leveraging genome wide CRISPR activation screening approaches, we were able to identify a previously uncharacterized regulator of IFN signaling (the ETS- family transcription factor ETV7) which upon induction, non-uniformly suppressed the expression of individual interferon stimulated genes (ISGs). The major goal of this application is to define this novel, ETV7 mediated, IFN regulatory mechanism and understand its physiological importance during influenza viral disease in vivo. In Aim 1, we will perform high-throughput biochemical analysis of ETV7 binding across all ISG promoters and then define how intrinsic ETV7 affinities for primary promoter sequences affect transcription factor competition. This work will reveal the first regulatory pathway capable of differential suppression of individual ISGs. In Aim 2, we will focus on understanding the cell type-specific importance of ETV7 regulation during respiratory epithelial innate immune responses and tissue regeneration after infection. These experiments will establish a new mechanism for how the balance between the antiviral signaling and regenerative capability in the lung is maintained. Finally, in Aim 3, we will explore how dysregulation of ETS-family transcription factors affects viral pathogenesis and recovery from infection in vivo. Successful completion of these studies will increase our understanding of the mechanisms that regulate IFN signaling during influenza virus infection and potentially inform new interventions to limit the severity of viral disease.


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 = $691,840 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	6	11/1/2024	NON-COMPETING CONTINUATION	$691,840
														Subtotal = $691,840

Issue Date FY: 2024 ( Subtotal = $713,913 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	002	5	9/3/2024	COMPETING CONTINUATION	$71,390
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	5	11/17/2023	COMPETING CONTINUATION	$642,523
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	11/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $713,913

Issue Date FY: 2022 ( Subtotal = $588,678 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	1/19/2022	NON-COMPETING CONTINUATION	$588,678
														Subtotal = $588,678

Issue Date FY: 2021 ( Subtotal = $595,976 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	1/22/2021	NON-COMPETING CONTINUATION	$595,976
														Subtotal = $595,976

Issue Date FY: 2020 ( Subtotal = $578,313 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	1/16/2020	NON-COMPETING CONTINUATION	$578,313
														Subtotal = $578,313

Issue Date FY: 2019 ( Subtotal = $570,450 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	1/10/2019	NEW	$570,450
														Subtotal = $570,450

Grand Total All Awards = $3,739,170

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ETS-family Transcription Factor Mediated Control of Pulmonary Inflammation Induced by Influenza Viruses

Award Number: R01AI137031

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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