Scientists strongly suspect a link between Zika and microcephaly, a disorder that causes abnormally small heads in newborns, but they're not entirely sure. Now, a team of researchers may have figured out how this mosquito-borne virus attacks the developing brains of foetuses — and wow, is it nasty. The latest research, published in Cell Stem Cell, suggests that Zika virus directly targets cells required for brain development, stunting their growth — and often destroying them outright. In particular, the virus is attacking and infecting what are called cortical neural progenitor cells — types of neural stem cells that give rise to the brain's cerebral cortex (the largest part of the human brain, and the part associated with higher brain function). Cellular growth is disrupted, and the cells often die. But the horror doesn't stop there; after these cells are exposed to Zika, the virus converts them into highly efficient factories for reproduction.
The researchers from Florida State University and Johns Hopkins Medicine were only able to study the effects of Zika on neural stem cells in a petri dish, so the study doesn't prove a direct link between the virus and microcephaly — but it's one hell of a smoking gun. For the first time, scientists have a good idea of where and how the virus does most of its damage.
"Although our findings may correlate with disrupted brain development, direct evidence for a link between disruption of cell growth with Zika virus infection and microcephaly is still missing," Zhexing Wen, a neurologist at Johns Hopkins University School of Medicine and a co-author on the study, explained in an email. "We still don't know at all what is happening in the developing foetus."
A doctor at Oswaldo Cruz Hospital examines a two-month-old baby with microcephaly on January 26, 2016 in Recife, Brazil. Credit: Getty.
The Zika virus is currently at epidemic levels in many parts of South America and the Caribbean, prompting the CDC to issue a travel advisory. While relatively harmless in most people, expectant mothers are considered at highest risk given the association between Zika and microcephaly.
This latest breakthrough in the war on Zika is a story unto itself. Last month, both the US Centres for Disease Control and the World Health Organisation asked scientists to expedite their research efforts. In response, Guo-li Ming and Hongjun Song of Johns Hopkins, with Hengli Tang of FSU, assembled a team of experts from four labs, all with different research interests. This multi-disciplinary team has been working around the clock for the past month trying to solve the mystery.
The researchers compared the virus's effect on human embryonic cortical neural progenitor cells (hNPCs) to two other cell types: induced pluripotent stem cells (cells that can give rise to any cell type in the body, including hNPCs) and immature neurons (hNPCs produce immature neurons). The researchers carefully studied the effects of the Zika virus on these cells, including genetic expression.
Illustration of normal cellular development of neural stem cells during neurogensis, from self-renewing progenitor cells (NPCs) to fully mature neurons. Zika is interfering with this developmental process at the first stage, preventing critical brain cells in the brain's frontal cortex from forming. Not only that, Zika hijacks NPCs, turning them into factories that produce even more Zika particles. Image: M. Resendiz et al., 2014
After just three days of Zika exposure, some 90 per cent of the hNPCs were infected, causing the hijacked cells to churn out new copies of the virus. The Zika infection increased cell death and disregulated cell cycle progression, dramatically slowing down hNPC growth. Disturbingly — and quite unusually — the genes required to fight the virus were not activated; the cell's built-in immune system remained idle after infection. It's as if the cells didn't know they were under attack. Many of the infected cells were killed, and damaged cells could no longer produce new cells.
"We're literally the first people in the world to know this, to know that this virus can infect these very important cells and interfere with their function," noted Tang in a statement.
This research shows that Zika is capable of infecting and compromising neuronal cells in a dish that are similar to the ones in the human cerebral cortex during brain development. But scientists still don't know what is happening in the developing foetus, or why symptoms in adults are so mild. They're also not sure how Zika enters the nervous system of the developing foetus, or how the virus is capable of crossing the blood-brain barrier. More ominously, they're not sure if Zika is capable of infecting the small population of neural stem cells that adults keep above the brainstem in the hippocampus.
Next, Wen says his team will "grow 3D mini-brains from human iPSCs [induced pluripotent stem cells]" to model the underlying cellular and molecular mechanisms of Zika infections — and hopefully develop drugs to treat or prevent the toll that Zika appears to take on developing brains.
Top image: Microscopic image showing cell death of the human neural progenitor cells. The Zika virus is shown in green, the brain cells in grey, and the breached brain cells in red. Credit: Sarah C. Ogden.