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PARP9-DTX3L Control Of Viral Infection and Airway Disease

Award Number: R01AI130591
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/21/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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PARP9-DTX3L Control Of Viral Infection and Airway Disease - Abstract A major goal of this proposal is to define the role of the airway epithelial cells in the immune response to respiratory viral infection and to extend this information to better control acute viral illness and prevent post- viral airway disease. Based on new insights into the issue of how airway epithelial cells mediate host defense against respiratory viruses, we will develop the hypothesis that the proper quality and quantity of interferon (IFN) signaling in airway epithelial cells is critical for controlling acute viral illness and post-viral airway disease. Studies of transgenic mice and transduced human cell lines further revealed that IFN signaling is limited by a PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin ligase that acted on host histone H2BJ to promote IFN-stimulated gene (ISG) expression and on viral 3C protease to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acts on host and pathogen to achieve a double layer of immunity within a safe reserve in the IFN signaling pathway and specially controls viruses like human rhinovirus (HRV) that require viral 3C protease for replication. We therefore hypothesize that airway epithelial cell PARP9-DTX3L specially regulates the severity of infection due to HRV and other picornaviruses like human enterovirus-D68 (HEV-D68) that might be more severe in patients with airway disease and/or linked to exacerbation or progression of airway disease. We also propose that the novel dual-mechanism for PARP9-DTX3L to safely harness IFN signaling reserve provides a roadmap to protect against respiratory viral infection and post-viral airway disease. Indeed, we used our findings to develop small-molecule IFN-signal enhancer (SMISE) compounds to enable the antiviral benefit of PARP9-DTX3L expression. To further develop these insights and translate them to practice, we have the following Specific Aims: 1. In human cell and molecular models, determine the role of PARP9-DTX3L in IFN signaling and control of respiratory picornaviruses in primary-culture human airway epithelial cells and recombinant human proteins. This Aim will also pursue the mechanism for PARP9-DTX3L activities and a structural biology approach to enhancing these actions. 2. In mouse cell and in vivo models, define the role of PARP9-DTX3L in IFN signaling and control of respiratory picornaviruses and post-viral airway disease using cell-specific transgenic, knock-out, and knock-in mice and airway epithelial cells from these mice. This Aim will develop new models of picornavirus infection and pursue the mechanism for PARP9-DTX3L activities in IFN signaling and SMISE effect. Together, the results will provide the first proof-of-concept for the role of PARP9-DTX3L in controlling respiratory picornavirus infection in vitro and in vivo and will advance the basis for developing an effective antiviral compound for this type of 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 = -$748 )
2024	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	5	8/22/2024	NON-COMPETING CONTINUATION	-$748
														Subtotal = -$748

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	5	1/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $608,777 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	5	1/21/2021	NON-COMPETING CONTINUATION	$608,777
														Subtotal = $608,777

Issue Date FY: 2020 ( Subtotal = $608,777 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	4	1/16/2020	NON-COMPETING CONTINUATION	$608,777
														Subtotal = $608,777

Issue Date FY: 2019 ( Subtotal = $608,777 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	1/2/2019	NON-COMPETING CONTINUATION	$608,777
														Subtotal = $608,777

Issue Date FY: 2018 ( Subtotal = $608,777 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	1/9/2018	NON-COMPETING CONTINUATION	$608,777
														Subtotal = $608,777

Issue Date FY: 2017 ( Subtotal = $608,777 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	2/21/2017	NEW	$608,777
														Subtotal = $608,777

Grand Total All Awards = $3,043,137

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PARP9-DTX3L Control Of Viral Infection and Airway Disease

Award Number: R01AI130591

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/21/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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