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.




Persistent LCMV infection rendered immature Schwann cells defective in myelin formation. Click to enlarge. Image courtesy of Proceedings of the National Academy of Sciences. Click to enlarge.