# Host Genetic Control of ZIKV Infection

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $45,520

## Abstract

Project Summary
Susceptibility to Zika virus (ZIKV) infection is highly variable. While most seropositive individuals remain
asymptomatic, approximately 18% develop symptoms that range from a mild rash in the majority of cases to
Guillain-Barré syndrome or microcephaly in the minority (less than 1% of neonates experience severe
pathology). Like all known vector-borne flaviviruses, ZIKV must evade type I interferon (IFN) signaling to
establish infection. IFNs are cytokines secreted by host cells in response to a pathogen that trigger the
establishment of an antiviral state in infected and neighboring cells via JAK/STAT-mediated transactivation of
over 400 IFN stimulated genes (ISGs). Recent evidence points strongly towards the degradation of the ISG,
signal transducer and activator of transcription 2 (STAT2) by non-structural protein 5 (NS5) as a putative
mechanism by which ZIKV escapes IFN, thereby implicating STAT2 as a dominant restriction factor in ZIKV
infection. As STAT2 is an essential component of the type I IFN signaling pathway, its removal abolishes all
canonical induction of ISGs. Notably, mice are resistant to both ZIKV and closely related dengue virus as their
NS5s do not inhibit murine STAT2, but STAT2-defcient mice are highly susceptible. This suggests that factors
that affect the ability of NS5 to clear host STAT2 impact disease outcome following infection.
Our group has previously identified rare germline mutations that confer resistance to a broad spectrum of viral
infections. Individuals deficient for ubiquitin specific peptidase 18 (USP18), a negative regulator of IFN, or for
IFN stimulated gene 15 (ISG15), a ubiquitin-like peptide that stabilizes USP18, exhibit elevated STAT2 levels
for up to 6 days post exposure to IFN. Dermal fibroblasts derived from ISG15-/- and USP18-/- individuals
showed 1,000 – 100,000 fold stronger inhibition of ZIKV replication when pretreated with IFNα-2b. We also
identified genetic variations in regions of STAT2 that likely alter the STAT2-NS5 interaction based on in silico
damage prediction, species specificity of NS5 for human, but not murine, STAT2, and common targeting of
STAT2 by NS5 from related flaviviruses. We therefore suggest that elevated STAT2 levels in ISG15-/- and
USP18-/- cells inhibit ZIKV by creating a stoichiometric imbalance that favors IFN signaling despite NS5-
mediated degradation of STAT2, and that heterogeneity within the STAT2 gene can explain differing levels of
disease.

## Key facts

- **NIH application ID:** 9847784
- **Project number:** 5F31AI138363-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Justin Taft
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-01-02 → 2021-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847784

## Citation

> US National Institutes of Health, RePORTER application 9847784, Host Genetic Control of ZIKV Infection (5F31AI138363-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9847784. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*