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Host Factors in Immunopathology

Strangely, aside from secondary infections, measles can cause a variety of effects in a patient—called immunopathologies—and determining the molecular causes of these is one area that interests Oldstone greatly.

Measles virus most often causes an acute infection accompanied by fevers and characteristic rashes. Frequently, though, it also causes a subacute infection characterized by severe brain disorders. And in some rare instances, measles causes a chronic, progressive disease.

This is one of the great mysteries of viral infections—how they can be so very different for different people. "How can the same virus cause three phenotypes?" asks Oldstone.

Oldstone is able to address this question experimentally. Several years ago, using transgenic techniques he developed the first in vivo models that carry the measles receptors and are susceptible to the virus. This allowed him and his laboratory to replicate a significant part of measles infection and learn about it.

The answer to the question of divergent phenotypes seems to lie in the field of both host genetics and viral immunopathology, in other words in the constellation of host factors and the way in which the virus interacts with them. These interactions determine the severity of the infection. The great majority of symptoms that occur during an acute infection are due to the reaction of the immune system.

"When you have an acute infection, the immune system is designed to terminate it," says Oldstone. "Either you get immunity or you get death."

But this depends on how widespread the infection is and where it takes place. If it takes place in the brain or the heart, the damage from the immune reaction might be so severe that the organism cannot recover. However, an infection that is localized in the skin might not be so severe.

Knowing what is turned on and off in the host organism and how these molecular switches can be switched back to normal is a major goal of Oldstone's research for another reason as well—it illuminates how viruses are able to persist in a host for years.

The Persistence of Viral Infections

In viral infections, a battle rages in the body. Sometimes this battle is won by the host, sometimes it is won by the virus, sometimes the host and the virus fight each other for years in a protracted war of attrition, and sometimes they coexist with remarkably little injury.

When a virus persists, the animal that is infected with the virus lives a natural life but may have specific dysfunctions. If the virus lives in the nerve cells, for instance, the learning functions of the animal can be impaired. If the virus replicates in the immune cells, the functioning of the immune system can be impaired.

"For a virus to persist, it has to evade the host immune system," says Oldstone.

Viruses often distort the function of cells, but in subtle ways. For instance, the GAP-43 gene, which is involved in cognitive function, can be turned off by lymphocytic choriomeningitis—a virus that Oldstone has studied for a number of years. The same virus can turn off the transcription factor that regulates the expression of growth hormone, which results in stunted growth.

"You don't see any distortion in the cells if you look at them under a microscope," says Oldstone. "The brain and pituitary gland look normal."

He looks at the mechanism, asking how the virus interacts with the host and how the host interacts with the virus. He also asks if this can be prevented.

Interestingly, when Oldstone began studying viruses, the prevalent theory at the time was that when viruses persisted, they did so because the host organism mounted no host response at all to the infection. In fact, Oldstone determined that this was not the case in the viral infections he looked at.

"I found that the host DID make an immune response," he says, "but the immune response was not enough to clear the infection."

And Speaking of History...

A few years ago, Oldstone wrote what might be considered an unusual book for an academic scientist. Unusual, that is, unless one considers the great tradition of literary scientists—Loren Eisley, Carl Sagan, and Stephen Jay Gould to name a few—who are both accomplished scientists and writers.

Perhaps as readers, we like to read scientist writers because their knowledge of the field is profound, and we trust them to guide us into the material—because we want to read about science, whether reflections on paleontology or evolution, or the galaxies, or time and space itself. We want to understand and we look to scientist writers who have an immediate intimacy with the subject matter.

And fascinating subject matter it is.

Viruses, Plagues, & History (Oxford, 1998) reads like a cross between Albert Camus and Steven Ambrose—a history wrapped in a narrative focused on a viral immunobiologist's history of viruses interacting with our immune system through time. His familiarity with the subjects allows him to move seamlessly from discussing 100-year-old measles outbreaks in Fiji to describing the immunopathology of the virus.

With chapters on smallpox, yellow fever, measles, polio, ebola, HIV, influenza, and other subjects, Viruses has a lot of material packed into its 230 or so pages. Still in its first edition, the book has recently been released in paperback and has been translated into several foreign languages, including Spanish, Polish, Chinese, Japanese, and even Hungarian.

"I've gotten invitations to speak about the book in several museums and colleges," says Oldstone. These include the Art and Science Museum in San Francisco and library and history departments of Ohio State, Montana, and Augustona College.

What led him to undertake such a huge effort late in his career? Like many of his contemporaries and many students of virology, medicine, and public health who would follow, Oldstone was inspired by Paul de Kruif's 1926 classic Microbe Hunters. And he had other ulterior motives as well.

"I thought it might be fun to entice undergraduates and graduates into the field," he says. "That's why I wrote the book."


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The top panel shows a single lymphocytic chorlomeningitis virus (LCMV)-specific CD8 T killer cell engaging three virus-infected cells in vivo in the brain. The bottom panel shows a single LCMV CD8 T killer cell that has deposited the chemical perforin on two virus-infected cells in the brain. Deposition of perforin is required to lyse the virus-infected cells and thus destroy them. (Data from studies by Dorian McGavern and M.B.A. Oldstone.)














An electron micrograph showing measles particles magnified 120,000 times. Micrography from studies by M.B.A. Oldstone and Peter W. Lambert.


















An electron micrograph showing lymphocytic choriomeningitis virus (LCMV) virions. Micrography from studies by M.B.A. Oldstone, Peter W. Lambert, and Michael Buchmeier.