Role of innate immunity in impaired neurodevelopment during zika virus infection

We will study neuroprogenitors by intraventricular injection of ZIKV into fetus of pregnant mice. We will assess the inflammatory signaling with high-throughput protein kinase/phosphatase assay.

Zika virus (ZIKV) is a global public health threat causing congenitaldisorders.  ZIKV infection duringpregnancy causes abnormal brain function and remarkably small heads (calledmicrocephaly) in newborns. Microcephaly is frequently caused by a problem inthe development of the brain cortex. The division, proliferation, anddifferentiation of neuron precursor cells (neuroprogenitors) are crucial forthe brain cortex development. Notably, ZIKV affects the function ofneuroprogenitors. However, mechanisms for ZIKV-induced dysfunction ofneuroprogenitors are not known. Determining how ZIKV causes defects onneuroprogenitors is a critical step to identify novel therapeutic targets anddevelop treatment of brain diseases.

Cholesterol is a crucial lipid component essential for neuroprogenitorfunction and proliferation. Alteration of cholesterol biosynthesis links to neurodegenerativedisorders. Cholesterol-25-hydroxylase (CH25H) is the enzyme convertingcholesterol to oxysterol (cholesterol derivative) and is involved in regulationof cholesterol homeostasis. Importantly, CH25H is induced during ZIKV infectionhaving anti-viral effect to inhibit ZIKV replication. Moreover, CH25H isproduced in response to stimulation with type I interferon. Our preliminarystudies demonstrate that other inflammatory cytokines, such as IL-1beta, arealso able to induce CH25H expression. These results suggest that innateinflammatory cytokines play a critical role in controlling ZIKV replication andZIKV-associated brain diseases.

Based on thesis findings, we hypothesize that inflammatory cytokines areresponsible for influencing ZIKV replication in fetus and their abnormal braindevelopment. To test this hypothesis, we will use an animal model of congenitalZIKV infection as well as a direct injection of ZIKV into fetus via intraventricularinjection. The impact of inflammatory cytokine signaling on ZIKV transmission andabnormal brain development will be profiled with high-throughput bioassays measuringprotein kinase and phosphatase signaling downstream of innate cytokines.

Desired outcomes

Expertise in virology, neurology, and systems biology will bringcomplementary scientific knowledge and technology together, leading to thesuccessful accomplishment of this project for the 3C Seed Grant application. Furthermore,findings will help to obtain external funding as well as provide a rationalbasis for the development of novel therapeutics for neurodegenerative diseases.