# Mechanisms and Modifiers of Zika Virus Innate Immune Evasion

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2021 · $194,148

## Abstract

Summary
Zika virus is a flavivirus that was first isolated in Uganda in 1947, and gained international notoriety during the
2015-2016 epidemic that spread to South America, North America, Pacific islands, and beyond (1-3).
Previously associated with a mild or asymptomatic infection transmitted by Aedes mosquitos, the American
Zika virus outbreak was associated with a greater incidence of microcephaly and Guillain Barré syndrome in
the children of women infected during pregnancy. Evidence for both sexual and asexual transmission of Zika
virus coupled with long latency periods continue to fuel public safety concerns. While experimental vaccination
strategies are being pursued, there are no known cures for Zika virus infection or specific prophylactic
treatments available for high risk professionals or individuals traveling to afflicted regions. Recent studies of
molecular pathogenesis and virulence factors used by Zika virus and other flaviviruses have uncovered a
general ability to disrupt or evade innate antiviral immune responses, primarily those mediated by type I and
type III interferon (IFN), making the viruses more resistant to exogenous IFN therapy and contributing to
virulence, tissue penetration, and host tropism. The flavivirus NS5 protein has been recognized as a primary
antagonist of IFN-JAK-STAT signaling, and both Dengue virus and Zika virus have been shown to use NS5 to
engage and destroy STAT2, an essential transcription regulator in the IFN response. While Dengue virus uses
a specific cellular ubiquitin ligase enzyme to target STAT2, Zika virus uses a distinct mechanism mediated by
unknown cellular machinery (13). Preliminary studies of Zika-mediated STAT2 degradation and IFN evasion in
human cells provided a foundation for the design of sensitive living cell-based assay systems to identify cellular
components used for STAT2 degradation and Zika virus replication. As mechanisms of virus host evasion are
hypothesized to be high potential targets for therapeutic intervention, two complementary aims are proposed to
(Aim 1) identify the cellular components required Zika NS5-mediated STAT2 degradation and (Aim 2) exploit
this pathway as a target for small molecule inhibition of Zika replication. Focusing initial hits from these
innovative experiments with general and mechanistic counter-screening and low-throughput follow-up analysis
will reveal missing mechanistic machinery needed for Zika virus-mediated IFN evasion, provide cellular targets
for investigations of virulence and pathogenesis to inform therapeutic interventions, and identify new leads for
Zika virus antiviral compounds.

## Key facts

- **NIH application ID:** 10168449
- **Project number:** 5R21AI148949-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** CURT M HORVATH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,148
- **Award type:** 5
- **Project period:** 2020-05-20 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168449

## Citation

> US National Institutes of Health, RePORTER application 10168449, Mechanisms and Modifiers of Zika Virus Innate Immune Evasion (5R21AI148949-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168449. Licensed CC0.

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