The terrible birth defects caused by Zika virus appear to be the result of an immune system response that triggers prenatal brain cell suicide and obstructs fetal brain development, a new lab study reports.
The virus apparently activates an immune receptor called TLR3, which the body uses to identify and defend against invading viruses, said lead researcher Tariq Rana. He is a professor of pediatrics and genetics at the University of California, San Diego.
The hyper-activated TLR3 then proceeds to turn off genes that fetal stem cells need to specialize into brain cells, and appears to switch on genes that trigger cell suicide, Rana said.
“We all have an innate immune system that evolved specifically to fight off viruses, but here the virus turns that very same defense mechanism against us,” Rana explained. “By activating TLR3, the Zika virus blocks genes that tell stem cells to develop into the various parts of the brain.”
These findings help explain how Zika causes microcephaly, an abnormally small brain and skull development, and other neonatal brain-related birth defects, Rana said. They also show why there’s no similar effect in adults, since their brains are already fully developed.
There’s also good news for the potential prevention of brain birth defects due to Zika. Rana and his team successfully blocked this process in laboratory stem cell samples by using a chemical that inhibits the action of TLR3.
A drug that safely blocks TLR3 could possibly save babies from birth defects if given to Zika-infected women during the early stages of pregnancy, he said.
“If some mom comes into the clinic and the doctor thinks there is a Zika infection established, you could give this med, and once the first trimester is done, you can take them off the med,” Rana suggested.
Zika is the first mosquito-borne virus ever proven to cause birth defects, according to the U.S. Centers for Disease Control and Prevention.
To figure out why this happens, Rana and his team used human embryonic stem cells to create a laboratory model of a first-trimester human brain, also called a “cerebral organoid.” The model’s stem cells were designed to specialize and grow into the various different cells in the brain, much the same as they do during a fetus’ first trimester.
Researchers then infected their model with Zika and found that a developing brain shrinks when exposed to the virus.
Five days after infection, Zika-infected organoids had decreased in size by an average 16 percent, the researchers found. By comparison, healthy brain organoids in a control sample had grown an average of 22.6 percent.
Rana’s team noticed that the TLR3 gene had been activated in the Zika-infected model brains.
TLR3’s job is to sense viruses and activate an immune response. But the researchers found TLR3 activation influenced 41 genes in the fetal brain and caused a disastrous chain-reaction that both prompted cells to die off and interfered with stem cells’ ability to grow into different brain cells.
By adding a chemical TLR3 inhibitor, Rana’s team found they could partially protect developing brain cells against Zika, although the virus still wound up doing some damage to their model brain.
Rana said this research has only been conducted in human and mouse cells, and needs to be replicated in actual organisms before it can be used to create any therapy to counter Zika.
But infectious disease expert Dr. Amesh Adalja called the work an “elegant study that begins to unravel how Zika is capable of causing microcephaly in the developing fetus.”
Adalja, a senior associate with the University of Pittsburgh Medical Center’s Center for Health Security, said, “We had known prior to this study that Zika had the capacity to infect neural progenitor cells and cause damage.”
With this study, he added, “we now have an elucidation of one mechanism that the virus uses, TLR3. This discovery opens up avenues for further understanding of the entire cascade of changes in gene expression that are caused by Zika infection.”
The study is published in the May 6 issue of the journal Cell Stem Cell.
For more on Zika virus, visit the U.S. Centers for Disease Control and Prevention.
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