The 3D stem cell-based fetal brain model provides first clues to the mode of action of the Zika virus, potentially leading to novel therapeutic options for affected patients.
Researchers at the University Of California San Diego School Of Medicine (CA, USA) have determined a way Zika infection could damage developing brain cells with a 3D stem cell-based fetal brain model. The study demonstrated that inhibiting this mechanism reduced brain cell damage, paving the way to a potential new therapeutic approach to mitigate the effects of prenatal Zika virus infection. The findings were recently published Cell Stem Cell.
The U.S. Centers 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.
Using a 3D stem cell-based model of a first-trimester human brain, the team discovered that Zika activates TLR3, a molecule used to defend against invading viruses in human cells. In turn, hyper-activated TLR3 inhibits genes that stem cells need to differentiate into brain cells whilst activating genes that trigger apoptosis, or cell suicide. When TLR3 was inhibited, the team observed reduced cell damage in the brain organoid model.
“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,” explained senior author Tariq Rana, from UC San Diego School of Medicine. “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.”
In the study, Rana’s team ensured their organoid model was truly representative of the early developing human brain. They found that the model’s stem cells differentiate into various cells of the brain in the same way that they would during the first trimester of human development.
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 whilst the Zika-infected organoids had decreased in size by an average of 16 percent.
To determine whether TLR3 activation could be the cause of Zika-induced organoid shrinkage (and therefore perhaps microcephaly) or merely a symptom of it, some of the infected organoids were treated with a TLR3 inhibitor. They found that the TLR3 inhibitor significantly tempered Zika virus’ severe effects on brain cell health and organoid size, underscoring TLR3’s role linking infection and brain damage. However, the treated organoids weren’t perfect. As evidenced by their non-smooth outer surfaces, infected but treated organoids still encountered more cell death and disruption than uninfected organoids.
While promising, the study was only conducted in human and mouse cells grown in vitro. In addition, the Zika virus strain used in this study (MR766) originated in Uganda, while the current Zika outbreak in Latin America involves a slightly different strain that originated in Asia.
“We used this 3D model of early human brain development to help find one mechanism by which Zika virus causes microcephaly in developing fetuses,” commented Rana, “but we anticipate that other researchers will now also use this same scalable, reproducible system to study other aspects of the infection and test potential therapeutics.”
Pardee K, Green AA, Takahashi MK et al. Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. Cell Stem Cell, doi: 10.1016/j.cell.2016.04.059 (2016) (Online before print); http://ucsdnews.ucsd.edu/pressrelease/zika_virus_may_cause_microcephaly_by_hijacking_human_immune_molecule