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Molecular mechanisms linking viral replication and neuropathogenesis

Award Number: R01AI170857
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: 02/08/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Molecular mechanisms linking viral replication and neuropathogenesis - PROJECT SUMMARY/ABSTRACT Viruses that infect the developing brain, including Zika virus (ZIKV), cytomegalovirus, and rubella virus cause major birth defects. Microcephaly is one such birth defect, in which head and brain size are severely reduced, and is often accompanied by intellectual disability. This virally-inflicted neurological disease, or viral neuropathogenesis, can be caused by multiple mechanisms. One recently identified way ZIKV non-structural protein 4A (NS4A) causes microcephaly is by disrupting the human ANKLE2 protein. Interestingly, individuals with mutations in the gene encoding ANKLE2 suffer from microcephaly. ANKLE2 is conserved from worms to humans, and is essential for coordinating cell division during brain development. ANKLE2 derives this function in cell division and development by mediating protein interactions. NS4A physically interacts with ANKLE2 and disrupts brain development in an ANKLE2-dependent manner in a fruit fly model of brain development. ANKLE2 also promotes ZIKV replication. Taken together, these studies show that in the process of coopting a host protein for replication, ZIKV dysregulates an important developmental pathway. Thus, the NS4A-ANKLE2 protein interaction represents an important model to study viral neuropathogenesis and how it is connected to viral replication and hereditary disorders at the molecular level. The long-term goal of this work is to decipher how virus-host protein interactions impact virus replication and pathogenesis, as these discoveries will fuel therapeutic target identification and drug development. The objective of this proposal is to dissect the mechanisms by which the protein interaction between ZIKV NS4A and human ANKLE2 promote ZIKV replication and inhibit brain development. To accomplish this objective, we will test the central hypothesis that ANKLE2 promotes viral replication through its interaction with NS4A and by recruiting other host factors involved in ZIKV replication to sites of replication, and this disrupts physiological ANKLE2 protein interactions required for brain development. The following specific aims will test this hypothesis: Aim 1: Dissect the impact of the NS4A-ANKLE2 protein interaction in ZIKV replication and pathogenesis. Aim 2: Unravel the molecular function of ANKLE2 in ZIKV replication and pathogenesis. When completed, this work will delineate how a single virus-host protein interaction rewires a developmental pathway to facilitate virus replication and inflict neurological disease at the molecular level. This will reveal detailed biochemical insight into a virus-host protein interaction with amino acid-level resolution, new host factors that play a role in ZIKV replication, and previously unknown proteins key to brain development and disrupted in other hereditary developmental disorders. In the long term, the methods established here could be employed to uncover the molecular mechanisms behind other diseases with viral and hereditary etiologies.


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 = $567,423 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	3	1/10/2025	NON-COMPETING CONTINUATION	$567,423
														Subtotal = $567,423

Issue Date FY: 2024 ( Subtotal = $979,229 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	002	2	5/23/2024	NON-COMPETING CONTINUATION	$54,849
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	001	2	1/25/2024	NON-COMPETING CONTINUATION	$493,647
2024	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	1	1/16/2024	NEW	$430,733
														Subtotal = $979,229

Issue Date FY: 2023 ( Subtotal = $391,009 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Allergy and Infectious Diseases Research	000	1	2/8/2023	NEW	$391,009
														Subtotal = $391,009

Grand Total All Awards = $1,937,661

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Molecular mechanisms linking viral replication and neuropathogenesis

Award Number: R01AI170857

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: 02/08/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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