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Learning how Japanese Encephalitis Virus debilitates brain cells

Leslee Lazar

JE affected districts in India
JE affected districts in India   (Photo: National Vector-Borne Disease Control Programme, http://nvbdcp.gov.in/je8.html)

Viral infections of brain cause a spectrum of diseases. Some are fatal, some leave lasting sensory, motor and cognitive deficits. One such important disease in the Indian context is Japanese Encephalitis (JE), caused by the Japanese Encephalitis Virus (JEV). A new study by scientists from National Brain Research Centre (NBRC), Manesar and University of Calcutta (UoC) has shown that JEV infection in human neural stem cells causes the host cell’s endoplasmic reticulum to malfunction, forcing infected neurons to die. The study was published in Cell Death and Disease .

The culprit virus JEV is transmitted by Culex tritaeniorrynchus- a mosquito that breeds in rice paddies. Apart from infecting humans, mosquitoes transfer the virus to several other animals (by biting them) like pigs, water birds, dogs and sheep, who act reservoirs of infection. In recent years, rise in population density, deforestation and expansion of irrigated agricultural land has increased the incidence of this disease. Children below 15 are especially vulnerable. Even in in patients who recover the acute phase of the disease, several are affected with a wide variety of cognitive impairments including learning disabilities, behavioural abnormalities as well as speech and movement disorders.

JEV is a flavivirus, with a single stranded RNA of approximately 1 Kb. Very little is known about the cellular mechanisms that enable JEV to infect neurons. Once it infects the cell, it hijacks the host’s protein synthesis machinery to replicate.

To better understand how JEV functions inside the host cell, researchers took help of neural stem cells to simulate JEV infection in human brain. “Studying viral infection in neural stem cells is important because, we can see exactly how viruses affect brain development. Viruses can delay or stop proliferation and differentiation of stem cells so there is reduced number of neuron and glia, which affects the overall brain function. They even kill the stem cells” says lead scientist Anirban Basu of NBRC.

The scientists infected cultures of human neural stem cells with JEV and studied the proteins synthesised in infected host cells. They found 13 proteins were present in abnormally high or low levels in JEV-infected human neural stem cells. These proteins are known to induce stress responses in the endoplasmic reticulum (ER).

The ER is a vital cell organelle that is important for folding, assembly and transport of the newly synthesised proteins from the nucleus. JEV infection lowers the protein folding capacity of ER and increases viral protein synthesis. This causes it to expand, leading to a stress response and eventually to apoptosis and cell death.

Three proteins; glucose regulated protein precursor (GRP78), prohibitin (PHB), and heterogeneous nuclear ribonucleoprotein C (C1/C2) (hnRNPC) were identified as the major targets in the pathway that causes ER-related stress response. Silencing of these proteins using siRNAs in the host stem cells decreased the effects of JEV infection. The same proteins were also found to be elevated in post-mortem brain tissue of patients who had died of JE.

This study sheds light on some of the cellular mechanisms involved in JEV infection in neural stem cells and offers potential targets for treating JE. Further research is needed to understand the role of stem cells in JEV aetiology and whether differentiated neurons have similar mechanisms of JEV infection. The effects of silencing these ER-stress related proteins in normal functioning of host cells also needs to be investigated. 

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