Scientists have for the first time found that Zika triggers cell suicide in the developing brain, a finding that may explain how the virus causes babies to be born with abnormally small heads and also help develop new therapies against the infection.
The US Center for Disease Control and Prevention recently concluded that Zika virus infection in pregnant women can stunt neonatal brain development, leading to babies born with abnormally small heads, a condition known as microcephaly. Now, researchers at the University of California San Diego found one way Zika can damage developing brain cells. They also found that inhibiting this mechanism reduces brain cell damage, hinting at a new therapeutic approach to mitigating the effects of prenatal Zika virus infection.
Using a 3D, stem cell-based model of a first-trimester brain, researchers found that Zika activates TLR3, a molecule human cells normally use to defend against invading viruses. In turn, hyper-activated TLR3 turns off genes that stem cells need to specialise into brain cells and turns on genes that trigger cell suicide.
“We all have an innate immune system that evolved specifically to fight off viruses, but here the virus turns that very same defence mechanism against us,” said Tariq Rana, Professor at UC San Diego.
“By activating TLR3, the Zika virus blocks genes that tell stem cells to develop into the various parts of the brain. The good news is that we have TLR3 inhibitors that can stop this from happening,” said Rana.
The researchers’ model closely resembled foetal brain tissue at eight to nine weeks post-conception.
When the team added a prototype Zika virus strain to the 3D brain model, the organoid shrank. Five days after the infection, healthy, mock-infected brain organoids had grown an average of 22.6 percent.
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In contrast, the Zika-infected organoids had decreased in size by an average of 16 per cent. Researchers also noticed that the TLR3 gene was activated in the Zika virus-infected organoids. TLR3 acts as an antenna, sensing double-stranded RNA specific to viruses. When viral RNA binds TLR3, it kicks off an immune response. TLR3 helps activate many different genes that aid in fighting an infection. However, in developing brain cells, TLR3 activation also influences 41 genes that lead to diminished stem cell differentiation into brain cells and increased cell suicide, a carefully controlled process known as apoptosis.
To determine whether TLR3 activation could be the cause of Zika-induced organoid shrinkage – and therefore perhaps microcephaly – or merely a symptom of it, researchers treated some of the infected organoids with a TLR3 inhibitor. They found that the TLR3 inhibitor tempered Zika virus’ severe effects on brain cell health and organoid size, underscoring TLR3’s role linking infection and brain damage. The study was published in the journal Cell Stem Cell.