# Zika Virus Capsid Protein Mediated Blockage of host microRNA machinery

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $434,033

## Abstract

SUMMARY
Zika virus (ZIKV) is a single-stranded RNA virus of the Flaviviridae family. It rapidly spread worldwide during
2015-2016 and is causally associated with fetal microcephaly, intrauterine growth retardation, and other
congenital malformations. ZIKV is reported to infect placenta and fetal brain during pregnancy, particularly
targeting human neural stem and progenitor cells (NSCs). Among the flavivirus family, only ZIKV is linked to
microcephaly, suggesting uniqueness of ZIKV infection compared to other members, which calls for a better
understanding of the molecular drivers of ZIKV immune evasion and pathogenesis in fetal brain. In addition, host
molecular targets of ZIKV proteins remain elusive, which not only limits our understanding of ZIKV infection and
pathogenesis, but also impedes anti-ZIKV drug development.
Since the ZIKV outbreak in 2015, we have focused on understanding the complexity of ZIKV infection and
pathogenesis of microcephaly. To fully understand the roles of viral proteins during ZIKV life cycle, we
established the ZIKV-host interactome in human iPSC-derived NSCs. By analyzing this ZIKV-host interactome,
we found that the key microRNA processing protein DICER was the top target of ZIKV capsid protein, and DICER
deficiency facilitated ZIKV infection in mouse embryonic NSCs. Dysregulation of microRNAs has been
associated with many human disease diseases, including developmental neurological disorders such as
microcephaly. More importantly, DICER-dependent microRNA production is commonly used by plants, fungi and
invertebrates, and remains active in mammalian stem cells to produce antiviral small RNAs from the viral
genomes, which inhibits viral replication via RISC-mediated RNA interference. Mechanistically, we further
identified that ZIKV capsid directly interacts with DICER and blocks its ribonuclease activity, dampening the
production of both viral interfering RNAs and host microRNAs that are essential for neurogenesis.
Therefore, we hypothesize that ZIKV can efficiently suppress the DICER-mediated antiviral viRNA pathway in
host cells with its capsid protein; and by antagonizing host microRNA machinery, ZIKV capsid also intervenes
neural development and causes microcephaly and other birth defects. Under the current application, we propose
to further investigate capsid-dependent suppression of DICER function as a unique determinant of ZIKV immune
evasion and pathogenesis, using different ZIKV strains and capsid variants in both human fetal NSCs and a
mouse model of prenatal infection. By understanding the unique role of DICER in ZIKV infection and its
associated microcephaly, we hope to define a capsid-dependent difference between the Brazilian and African
strains (AIMs 1-2), and provide a proof-of-concept whether boosting this viRNA-dependent innate immune
system is applicable as a novel approach to reverse the pathogenesis of ZIKV in fetal brain (AIMs 2-3). The
outcomes of this application will also provide broader i...

## Key facts

- **NIH application ID:** 10093159
- **Project number:** 5R01NS110687-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Zhen Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $434,033
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093159

## Citation

> US National Institutes of Health, RePORTER application 10093159, Zika Virus Capsid Protein Mediated Blockage of host microRNA machinery (5R01NS110687-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10093159. Licensed CC0.

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