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.

Public Health Relevance

Zika virus (ZIKV) has been associated with congenital Zika syndrome (CZS) in fetuses and infants, including microcephaly, spontaneous abortion, and intrauterine growth restriction. The proposed project will investigate the role of Pellino (Peli)-1 in ZIKV pathogenesis and identify the mediators responsible for alterations in brain development for prevention and treatment of CZS.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Davis, Mindy I
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University of Texas Med Br Galveston
Schools of Medicine
United States
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