Researchers Discover How Zika Virus Causes Fetal Brain Damage
According to a team of researchers led by Yale University, infection by the Zika virus diverts a key protein necessary for neural cell division in the developing human fetus. The findings, published in the journal Cell Reports , suggest that Zika virus might be susceptible to existing antiviral drugs that may prevent disruption to the developing nervous system.
Marco Onorati et al . describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and Zika virus (ZIKV)-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, the team shows that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. The scientists also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. They established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment. Image credit: Marco Onorati et al .
One of the side-effects of Zika virus infection in pregnant women is the risk of fetal microcephaly, in which babies are born with abnormally small brains.
The Yale-led team revealed that the virus kills stem cells in the brain and disrupts the process of creating brain cells.
An analysis shows that the virus diverts a form of the protein TBK1 from its primary job of organizing cell division to the mitochondria, where it helps initiate an immune response.
Lacking the protein at the site of cell division, cells die instead of forming new brain cells, resulting in microcephaly.
The data suggest this mechanism may also contribute to microcephaly associated with other common congenital viral infections.
“An existing FDA-approved drug, Sofosbuvir, showed promise in preventing Zika virus infection of neural stem cells in lab culture and also seems to keep phospho-TBK1 involved in cell division,” the scientists said.
“More study needs to be conducted to prove the efficacy of the drug as a medical therapy for Zika virus.”
“There is an urgent need to identify therapeutic approaches to halt Zika infection, especially in pregnant women,” said co-first author Dr. Marco Onorati, a researcher in the Department of Neuroscience and Kavli Institute for Neuroscience at the Yale School of Medicine.
“In the interim, we hope these findings can lead to therapies that might minimize the damage caused by this virus.”