A Lesson for Lassa
By Jason Socrates
Bardi
Lassa fever is something of an enigma.
An acute viral illness named after the Nigerian village
where it was first discovered in 1969, Lassa is an extraordinarily
deadly disease caused by a single-stranded RNA virus. Hundreds
of thousands of people a year contract Lassa fever when they
come into contact with this virus, which is shed by a small
rodent common to West Africa. Lassa infections can be severe,
causing hemorrhagic fever and killing up to a third to a half
of those infected in some outbreaks.
The enigma of Lassa is that it can be so deadly that its
other, non-lethal effects may be overlooked during the life-threatening
acute stage of infection. Lassa also causes neurological disorders
and is one of the major causes of hearing loss in areas where
the disease is transmitted. Each year, thousands die from
Lassa fever infections, but hundreds of thousands may suffer
some form of deafness as a result.
About a third of all patients who survive a Lassa infection
suffer some hearing loss, and many survivors are left permanently
deaf. But despite the fact that scientists and health care
workers have recognized this for many years, the way in which
Lassa fever causes hearing loss has not been known.
Now, Professor Michael B. A. Oldstone and Senior Research
Associate Stefan Kunz of The Scripps Research Institute are
reporting a possible mechanism for how Lassa fever virus causes
hearing loss.
Not Just Another Arenavirus
Lassa and a similar virus called Lymphocytic choriomeningitis
virus, or LCMV, are both members of the arenaviridae family
of viruses—nasty viruses that cause chronic, smouldering
infections in rodents and acute, deadly outbreaks of disease
in humans. LCMV is more than just another arenavirus, though.
Discovered in 1933, LCMV is the prototype for this family.
"Many of our basic concepts in immunology and virology have
come from work with this virus," says Oldstone. Fundamental
insights discovered by scientists working with LCMV include
mechanisms like T cell recognition, major histocompatability
complex restriction, understanding how a virus infects immune
cells and suppresses immune responses, and discovering how
a virus can establish a persistent infection and can cause
disorders related to that infection. These findings have paved
the way for discovering the mechanisms of other viral infections—such
as HIV and hepatitis.
Oldstone has made a career of studying host-virus interactions
and his work has been recognized with numerous prizes, including
the J. Allyn Taylor International Prize in Medicine. A few
years ago, while studying LCMV, Oldstone discovered that the
receptor for Lassa fever virus and LCMV is the protein a-dystroglycan.
If scientists prevent binding of the virus to that receptor,
they can prevent infection from occurring.
The a-dystroglycan receptor is
displayed on the surface of numerous human cells, but has
heightened expression on endothelial cells, which line blood
vessels, dendritic cells, which are important for antigen
presentation in the immune system, and Schwann cells, which
are important for the formation of myelin sheaths in the peripheral
nervous system.
The virus doesn't kill these cells—it just turns off
their function. And that suppression can cause widespread
bodily harm. Death is caused in part by the suppression of
the dendritic cells, which in turn suppresses the immune system.
And the mucosal bleeding that is often observed in Lassa fever
may be related to the infection of endothelial cells lining
blood vessels.
In a recent article published by the Proceeding of the
National Academy of Sciences, Oldstone, Kunz, and their
collaborator Anura Rambukkana of The Rockefeller University
report that the hearing loss that often accompanies infections
with Lassa fever virus is likely related to the virus glocoprotein
binding to a-dystroglycan receptors
on Schwann cells in the peripheral nervous system. Lassa fever
virus uses these a-dystroglycans
to gain entry and then suppresses the function of the Schwann
cells.
The Myelin Pays in an Infection
Schwann cells are responsible for wrapping the axons of
peripheral neurons with sheaths of myelin—concentric
layers of cell membrane. The myelin insulates the neurons
and allows for the transmission of action potentials down
these long neurons when they fire. Without myelin, neurons
lose their ability to effectively transmit a signal. Thus,
Schwann cells play a crucial role in the peripheral nervous
system.
Schwann cells have an incredible amount of a-dystroglycan
on their surface, says Oldstone, and when they are infected
by Lassa fever virus, they lose the ability to form myelin
basic proteins and to wrap the neurons with myelin sheaths.
This loss is related to the viral glycoprotein—a protein
on the surface of the virus that it uses to recognizes the
a-dystroglycan receptor and gain
entry into a Schwann cell.
On binding to the Schwann cell, this glycoprotein also interferes
with a structure on the outer surface of the cell membrane
referred to as the laminin. Laminins are a family of large
proteins of the extracellular matrix, which surrounds most
cells in tissues of higher organisms. Laminin proteins are
heterotrimers with a, b,
and g chains that contain binding
sites for several types of cellular receptors, such as integrins,
and dystroglycan. The interaction of laminins with their cellular
receptors anchor cells in their tissue environment and are
also involved in cellular differentiation and normal function.
On infected Schwann cells, the viral glycoprotein binds
with higher affinity than laminin does to a-dystroglycan,
so the laminins are pushed aside. This effectively disorganizes
the extracellular matrix and is associated with the Schwann
cells' inability to form myelin.
Without the myelin sheaths, peripheral neurons lose their
ability to transmit signals to and from the central nervous
system. If this happens to auditory neurons, the result can
be deafness.
The work is also significant because it provides scientists
with a model system for studying the process of cell myelination
and demyelination in living cells.
The article, "Targeting Schwann cells by nonlytic arenaviral
infection selectively inhibits myelination" was authored by
Anura Rambukkana, Stefan Kunz, Jenny Min, Kevin P. Campbell,
and Michael B. A. Oldstone and can be found at http://www.pnas.org/cgi/content/abstract/2232366100v1.
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