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Loss of cellular identity after influenza virus infection and effects on pulmonary function

Award Number: R01HL142985
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Loss of cellular identity after influenza virus infection and effects on pulmonary function - Project Summary/Abstract Influenza viruses infect an estimated 20% of the global population every year and although infection is typically highly acute, influenza viruses can induce prolonged changes to host pulmonary physiology. Due to their importance for global health, influenza viruses are well studied; however relatively little work has been done investigating the fates of infected epithelial cells. This is primarily because the dogma in the field has long held that influenza viruses are exclusively cytopathic viruses, i.e. all infected cells are eventually killed. We were interested in experimentally determining if any cells could survive direct viral infection and potentially continue to affect the host after viral clearance. Using recombinant strains of influenza A virus (IAV) and influenza B virus (IBV), along with transgenic animal systems to monitor the fates of infected cells, we found that up to 3% of the lung epithelium is infected but is not killed by the virus or the subsequent immune response. While the survival of some epithelial cell types was virus specific, both IAV and IBV induced the formation of populations of “survivor” ciliated cells. Ciliated cells are a terminally differentiated cell type with a well characterized morphology and transcriptional profile, which we hypothesized would be a powerful model to identify and interrogate any long-term effects of viral infection on cellular physiology. We found that viral infection induced a striking loss of the normal ciliated cell identity which not only allowed the expression of genes normally restricted to other epithelial cell types, but also caused morphological and functional changes that were important for the preservation of pulmonary function after infection. In this proposal, we attempt to leverage these observations and experimental models to understand how viruses can affect cellular identity, as well as how cellular identity flexibility relates to viral pathogenesis. The proposed experiments will reveal not only how viral infection can break the normal rules of cellular differentiation, but also reveal a novel host adaptive mechanism to maintain critical organ function during acute viral infection. Long term, the results of this study may also reveal cellular processes that can be therapeutically exploited to improve the outcome of influenza virus infection. !


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: 2024 ( Subtotal = -$216 )
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Lung Diseases Research	000	5	9/25/2024	NON-COMPETING CONTINUATION	-$216
														Subtotal = -$216

Issue Date FY: 2022 ( Subtotal = $588,098 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	000	5	6/20/2022	NON-COMPETING CONTINUATION	$588,098
														Subtotal = $588,098

Issue Date FY: 2021 ( Subtotal = $609,414 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	000	4	6/25/2021	NON-COMPETING CONTINUATION	$609,414
														Subtotal = $609,414

Issue Date FY: 2020 ( Subtotal = $568,858 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	000	3	7/9/2020	NON-COMPETING CONTINUATION	$568,858
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	002	2	8/29/2020	NON-COMPETING CONTINUATION	$0
2020	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	001	1	8/28/2020	NEW	$0
														Subtotal = $568,858

Issue Date FY: 2019 ( Subtotal = $555,794 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	000	2	7/1/2019	NON-COMPETING CONTINUATION	$555,794
														Subtotal = $555,794

Issue Date FY: 2018 ( Subtotal = $506,729 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Lung Diseases Research	000	1	6/29/2018	NEW	$506,729
														Subtotal = $506,729

Grand Total All Awards = $2,828,677

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Loss of cellular identity after influenza virus infection and effects on pulmonary function

Award Number: R01HL142985

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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