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Perturbation of Host DNA Replication and Cell Cycle Progression by Zika Virus

Award Number: R01AI146342
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: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Perturbation of Host DNA Replication and Cell Cycle Progression by Zika Virus - The broad, long-term goal of our research program is to advance knowledge of virus–host cell interactions that are relevant for disease prevention. The viruses that we study are positive- strand RNA viruses such as dengue virus (DENV), hepatitis C virus (HCV), and Zika virus (ZIKV). The current proposal focuses on ZIKV, which has re-emerged worldwide and poses a major emerging threat to human health. Understanding how ZIKV interacts with the host cell is of critical importance to the development of antiviral drugs and a prophylactic vaccine, both of which are currently lacking. Building upon our recently published work on the infection and impact of ZIKV on human neural stem cells, we propose to unravel the mechanism by which ZIKV impedes the growth of human cortical neural progenitor cells (hNPCs) and leads to defects in cortex development. Our preliminary data indicate that part of the mechanism for cell cycle arrest is a ZIKV-induced DNA damage response (DDR) which blocks DNA replication and leads to S-phase arrest. Unexpectedly, the ATR/Chk1 DNA checkpoint pathway that normally functions to deal with DNA replication stress in S-phase was not activated, suggesting that ZIKV suppresses ATR/Chk1 activation during DNA replication. The ability to increase DNA replication stress while simultaneously inhibiting ATR responds constitute a potent “one-two punch” that exacerbates replication defects and ultimately leads to cell cycle arrest. We will carry out experiments to investigate the mechanisms by which ZIKV achieve these feats and identify the viral proteins responses. We will also cross-validate our results with brain organoids and infectious clones of Zika/Dengue chimeric viruses. We expect to clearly understand the mechanisms by which ZIKV perturbs the cell cycle to achieve its pathological effect on hNPC-mediated neural development in vitro. We also expect to reveal the virulent determinant of ZIKV critical for its effect on brain development. These results will not only fundamentally advance our understanding of this important human pathogen but also provide direct and immediate impact on the mission to develop effective therapy to treat ZIKV infection and its associated diseases.


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: 2027 ( Subtotal = -$4,903 )
2027	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	5	11/2/2026	NON-COMPETING CONTINUATION	-$4,903
														Subtotal = -$4,903

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	5	5/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $378,755 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	5	6/30/2023	NON-COMPETING CONTINUATION	$378,755
														Subtotal = $378,755

Issue Date FY: 2022 ( Subtotal = $378,817 )
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	4	6/15/2022	NON-COMPETING CONTINUATION	$378,817
														Subtotal = $378,817

Issue Date FY: 2021 ( Subtotal = $378,878 )
2021	2021	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	3	6/10/2021	NON-COMPETING CONTINUATION	$378,878
														Subtotal = $378,878

Issue Date FY: 2020 ( Subtotal = $378,939 )
2020	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	2	6/11/2020	NON-COMPETING CONTINUATION	$378,939
														Subtotal = $378,939

Issue Date FY: 2019 ( Subtotal = $378,998 )
2019	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Allergy and Infectious Diseases Research	000	1	6/14/2019	NEW	$378,998
														Subtotal = $378,998

Grand Total All Awards = $1,889,484

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Perturbation of Host DNA Replication and Cell Cycle Progression by Zika Virus

Award Number: R01AI146342

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: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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