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
Death and Disease .
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
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.
scientists infected cultures of human neural stem cells with JEV and
studied the proteins synthesised in infected host cells. They found
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
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.
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.
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.