# JAK-STAT Control of Zika Virus-Induced Fetal Injury

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $875,928

## Abstract

PROJECT SUMMARY/ABSTRACT
The recent epidemic of Zika virus (ZIKV) in the Americas was deemed a global public health emergency after an
unexpected surge in congenital microcephaly cases suggested that the virus was teratogenic in pregnancy. ZIKV is
a flavivirus, primarily transmitted to humans by the bite of infected mosquitoes. ZIKV can infect a variety of placental
cells and is also highly neurotropic to target neural progenitor cells, astrocytes and neurons in all stages of
development. The congenital ZIKV syndrome describes a severe pattern of placental and fetal brain injury
associated with pregnancy infection including microcephaly, ventriculomegaly, and ocular injury. Although the
epidemic is now in decline, outbreaks will recur and the US remains at risk for an epidemic. Thus, an enduring need
remains to define the viral-host interactions that support ZIKV infection, replication, and maternal-fetal transmission,
and to develop a clinically relevant animal model for studies of pathogenesis. Relevant animal models are essential
to define the outcome of viral-host interaction within the progression of ZIKV infection and to evaluate the efficacy
of vaccines and therapeutics to control ZIKV infection and emergence. We have developed a highly relevant
nonhuman primate model of the congenital ZIKV syndrome (Macaca nemestrina, pigtail macaque) in addition to
clinically relevant in vitro and ex vivo models of placental and neural stem cell infection. We have shown that ZIKV
(1) mediates a broad blockade to the JAK-STAT pathway in infected cells to abrogate cytokine signaling mediated
by STATs 1-6, to suppress interferon antiviral defenses; (2) infects trophoblast, myeloid, epithelial, and neural
progenitor cells to impose a JAK-STAT blockade through the actions of viral nonstructural protein(s); (3) infects a
variety of maternal and fetal tissues in our nonhuman primate model including the neural progenitor cells in the
developing fetal brain, and (4) infection reprograms the STAT-dependent fetal brain transcriptome in vivo to alter
developmental gene networks. In this resubmission, we present new preliminary data to reveal that ZIKV NS5
binding to HSP90 disrupts the essential interaction of Jak and Tyk2 kinases with HSP90 that otherwise promotes
kinase folding and function. The ZIKV NS5-HSP90 interaction suppresses JAK-STAT signaling to abrogate
interferon antiviral defenses, which also presents a blockade to cytokine-directed cell-fate decisions signaled via the
JAK-STAT pathway that, in part, underlie ZIKV disease. Our central hypothesis is that acute ZIKV infection
induces a broad blockade of JAK-STAT signaling involving multiple STATs to suppress antiviral defenses,
which enhances vertical transmission and alters fetal brain development. In Aim 1, we will determine how
ZIKV mediates a broad JAK-STAT signaling suppression (STAT 1-6) in vitro and ex vivo to control innate immune
defenses, viral trafficking and injury. A new feature of Aim 1 is t...

## Key facts

- **NIH application ID:** 9962294
- **Project number:** 5R01AI143265-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Kristina M. Adams Waldorf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $875,928
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962294

## Citation

> US National Institutes of Health, RePORTER application 9962294, JAK-STAT Control of Zika Virus-Induced Fetal Injury (5R01AI143265-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9962294. Licensed CC0.

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