Pellino-1, a novel target for treatment of congenital Zika syndrome - Project Summary
Zika virus (ZIKV) a newly emerging mosquito-borne Flavivirus, has been associated with the neurological
autoimmune disorder Guillain-Barre syndrome in adults and congenital Zika syndrome (CZS) in fetuses and
infants, including microcephaly, spontaneous abortion, and intrauterine growth restriction. Currently, neither
treatments nor approved vaccines are available for use in humans to protect against ZIKV infection. It has
been reported that ZIKV infection of susceptible pregnant dams led to placenta damage and virus transmission
to the fetus. Placental trophoblasts are epithelial cells that invade and remodel the uterine wall during
placentation and are permissive to ZIKV infection. Human neural stem or progenitor cells (NS/PCs) were more
susceptible to ZIKV replication than mature cortical neurons. ZIKV induces more cell death in human NS/PCs
than in mature cortical neurons and dysregulates cell-cycle progression, resulting in attenuated cell growth.
Inflammation is a critical contributor to both normal development and injury in the immature brain. Intrauterine
ZIKV infection during early pregnancy was reported to cause placental inflammation, and a reduction of
neonatal brain cortical thickness. ZIKV- induced toll-like receptor 3 activation in human cerebral organoids was
accompanied by depletion of NS/PCs. Our collaborator of this project, Dr. Ping Wu, has recently shown that
ZIKV- induced differential innate immune responses, particularly, inflammatory cytokine production correlates
with alterations in neuronal differentiation among NS/PCs. Thus, direct ZIKV infection and/or ZIKV- induced
inflammatory responses in placental trophoblasts and NS/PCs contribute to CZS formation. Pellino (Peli)-1, an
E3 ubiquitin ligase, is a positive regulator in pathogen recognition receptor- mediated inflammatory cytokine
responses. It is expressed on many cell types and is enriched in the central nervous system (CNS) tissues. We
have recently found that Peli1 is required for viral replication and induction of inflammatory cytokines and
chemokines in microglial cells and neurons during another falvivirus- West Nile virus infection. We also found
that Peli1 expression was upregulated in human NS/PCs following ZIKV infection. Treatment with the Peli1
inhibitor Smaducin6 reduced both viral load and inflammatory cytokine production in ZIKV-infected NS/PCs.
The long-term goal of our project is to understand the molecular and immune mechanisms of ZIKV-induced
neurological diseases. Specifically, we hypothesize that Peli1 promotes ZIKV infection, induction of
inflammatory immune responses and cell death, resulting in impaired neurogenesis and CZS. We will first
determine the role of Peli1 in an in vitro model of CZS. Next, we will evaluate the therapeutic effects of
Smaducin6 in animal models of CZS. Results from this study will provide important insights into ZIKV
pathogenesis. In addition, identifying the mediators responsible for alterations in brain development is key to
prevention and treatment of CZS.
