Give Me Immunity or Give Me Death

By Jason Socrates Bardi

Having been among the early converts, in this part of the globe, to [smallpox vaccine's] efficiency, I took an early part in recommending it to my countrymen. I avail myself of this occasion of rendering you a portion of the tribute of gratitude due to you from the whole human family. Medicine has never before produced any single improvement of such utility.

———Thomas Jefferson, from a letter to Edward Jenner, 1806

When Meriwether Lewis and William Clark began planning their mission of exploring the American West, they received a special package from President Thomas Jefferson, who had commissioned Lewis to lead the expedition.

Jefferson instructed Lewis to carry with him Jenner's smallpox vaccine and distribute it to the Indian tribes throughout the West, many of which had already sustained outbreaks of smallpox. Variola, the virus that causes smallpox, had continued its expansion into the new world.

"Inform those of them with whom you may be, of it's efficacy as a preservative from the smallpox & instruct & encourage them in the use of it," said Jefferson.

Jefferson was hoping that the vaccine—which contained live cowpox virus—could possibly stave off smallpox epidemics among the immunologically naïve western tribes, whose landmass isolation had allowed them to escape the devastating disease.

Sadly, though, the vaccine did not survive the journey west. And within a few decades, smallpox outbreaks with mortality rates as high as 90 percent would devastate many of the western tribes.

"The history of these things is quite interesting," says Michael B. A. Oldstone, a professor in the Department of Neuropharmacology at The Scripps Research Institute (TSRI), who is equally interested in viruses themselves.

Small, Significant

The smallpox virus belongs to a family of nature's most ruthless killers—the RNA viruses, which are among the oldest and most notorious adversaries the human species has ever had, and which Oldstone has spent a career studying.

They range from measles, mumps, and rubella virus to the viruses that cause foot and mouth disease, polio, hepatitis A and C, yellow fever, human immunodeficiency virus, and the "Spanish Flu" influenza virus, which killed more Americans in World War I than died in combat.

In this day and age of solving genomes and mapping the expression of thousands of genes to particular tissues, RNA viruses are somewhat of a paradox. On the one hand, they can bring societies to their knees. Smallpox killed more people in the 20th century than died in all the century's wars combined.

On the other hand, RNA viruses are rather unassuming. They are like the old VW bugs of the pathogen world—small, simple, and seemingly able to run forever. An RNA virus can have as few as four genes. Nearly all of them have under 10 genes. The largest RNA virus has only 12 genes.

Yet, RNA viruses are able to alter cell function and profoundly affect the complex, eukaryotic life forms that they infect. An RNA virus with only four genes can cripple or kill a mammal with 40,000 genes.

Take the choriomeningitis virus, for instance, one of the viruses that Oldstone has studied for several years. Its genome is segmented into two separate pieces of RNA that are packaged together. They are packaged inside a compact virion, an infectious virus particle. And together, the entire genome is only a few thousand bases—six orders of magnitude smaller than the cells it infects—and has only four genes. Yet it can easily persist for the lifetime of that organism.

"Everything the virus needs is in these four genes—it's amazing," says Oldstone, adding that, by comparison, herpes virus has 250 genes.

This leads one to ponder—as it led Oldstone to puzzle over years ago—how, with so few genes, these RNA viruses are able to do what they do. At the outset of his career, Oldstone decided to ask, specifically, what are the host factors that are involved in the infection? What proteins and other molecules in the infected organism are the viruses interacting with? And how can we use the tens of thousands of genes in our brains to stop those handful of viral genes? His work in this area since he began his career at TSRI has led to recognition and many awards, including the J. Allyn Taylor International Prize in Medicine for the study of host–virus interactions.

The Most Contagious of Them All

One of the viruses that Oldstone has studied for a number of years, measles, is the most contagious infectious agent known to humankind.

With an infection rate of 98 to 99 percent, measles is a highly infectious virus that causes a maculopapular rash, fevers, diarrhea, and, one to two times out of a thousand, death. Measles is also highly contagious, and until the advent of mandatory vaccination programs in the United States, there were an estimated three to four million cases annually. Some 90 percent of the U.S. population had had measles by the age of 15.

There has been a commercially available vaccine for measles in use since 1963, and, though effective, this vaccine must be kept refrigerated for the duration of its one-year shelf life. This is problematic in tropical climates like southern Asia and sub-Saharan Africa, which continue to support endemic measles infection. The World Health Organization (WHO) estimates that in 2001 there were 30 million cases of measles worldwide and over one million deaths.

The measles virus has eight genes and gets a lot of use out of them, infecting lymphocytes, dendritic cells, and cells of the nervous system. The viral receptors that facilitate the entry of measles into cells are known, and one of these receptors, called CD46, is of particular interest to Oldstone. The measles virus has a hemagglutinin glycoprotein that binds to a single, broad surface on one side of CD46, which is expressed on virtually all cells in the body, and as a result, measles virus can infect multiple organs, including the brain.

Cases of measles can be severe when the virus infects the brain, because the body's immune response can cause massive damage to the central nervous system, and about one out of every million cases results in a chronic, progressive, fatal neurological disease.

However, mortality from measles is usually much higher than this because the disease is immunosuppressive—it infects cells of the immune system—and if "opportunistic" infectious agents like Mycobacterium tuberculosis or Staphylococcus are present, the immunosuppression can lead to a secondary infection, which is often fatal. Measles mortality can be is as high as 33 percent.

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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Michael Oldstone, professor at TSRI, is also the author of a historical narrative, Viruses, Plagues, & History.













Measles, the most contagious infectious agent known to humankind, has afflicted many societies, as this drawing by a sixteenth-century Aztec shows. Drawing from the Códue Florentino.













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.