doi:10.1038/nindia.2018.93 Published online 27 July 2018
When the Zika virus strikes unborn babies, it reduces the pool of brain cells in the foetus. As a result, the baby is born with a condition called microcephaly or a significantly smaller head size than a normal baby. What happens at the molecular level during such a virus attack has been a mystery.
A group of Indian scientists at the National Brain Research Centre in Haryana have now identified the cellular and molecular mechanisms of what exactly causes microcephaly. They have found that the culprit is a protein – the Zika virus Envelope (E) protein – that affects normal properties of brain stem cells and is the reason behind the abnormality in babies affected by this mosquito-borne disease1. The study provides several novel insights into understanding the pathology of Zika virus and could aid diagnosis and treatment of the disease caused by the Aedes Aegyptii mosquito.
Using stem cells from human foetuses, NBRC scientist Pankaj Seth and colleagues tried to understand how proteins of the Zika virus affect properties of the cells during the baby’s development in the womb. In lab cultures, they over-expressed several Zika virus proteins in brain stem cells and studied the effect on the proliferation of the cells. The researchers noticed that out of all the viral proteins studied, the Zika virus Envelope (E) protein caused maximum increase in the number of cells.
Seth’s Ph.D student Reshma Bhagat identified that the protein promoted premature but faulty formation of neurons, the functional units of the brain. “This suggested that E protein affects normal properties of brain stem cells and could be the reason behind Zika virus-induced small head size in babies,” she says.
They collaborated with neuroscientist Jonaki Sen at the Indian Institute of Technology Kanpur to validate these findings in mouse pups. The team found that over-expressing the E protein in mouse foetuses while they were still in the wombs significantly decreased their brain stem cell numbers.
The researchers also identified certain micro RNAs – which regulate genes and protein expression in cells – as important factors that impacted the cell division, proliferation and ‘stemness’ of the brain stem cells. In a global miRNA analysis, Seth and colleagues identified 25 miRNAs that significantly changed due to over-expression of the E protein in brain stem cells.
The World Health Organization (WHO) has recognised a strong correlation between the incidence of microcephaly in babies born to Zika-infected pregnant women, especially after the recent outbreaks in Brazil and a few other countries. Zika infections were also reported in India in 2017.
Seth, who has earlier worked on the effect of HIV-1 proteins on the human brain, says this is the first detailed study of the mechanism of Zika virus in India and among a very few neuroscience-based perspectives around the world on human neural stem and precursor cells from foetal brains.
1. Bhagat, R. et al. Zika virus E protein alters the properties of human fetal neural stem cells by modulating microRNA circuitry. Cell Death Differ. (2018) doi: 10.1038/s41418-018-0163-y