# Molecular mechanisms linking viral replication and neuropathogenesis

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $528,198

## Abstract

PROJECT SUMMARY/ABSTRACT
Viruses that infect the developing brain, including Zika virus (ZIKV), rubella virus, and cytomegalovirus, 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 mechanism by which 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 is not an
enzyme, and instead 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 interaction with amino acid-level resolution, new host factors that
play a role in ZIKV replication, and previously unknown proteins key to brain development. In the long term, the
methods established here could be employed to uncover the molecular mechanisms behind other diseases with
viral and hereditary etiologies.

## Key facts

- **NIH application ID:** 10673233
- **Project number:** 1R56AI170857-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Priya Shirish Shah
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $528,198
- **Award type:** 1
- **Project period:** 2022-08-19 → 2023-02-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10673233

## Citation

> US National Institutes of Health, RePORTER application 10673233, Molecular mechanisms linking viral replication and neuropathogenesis (1R56AI170857-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10673233. Licensed CC0.

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