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The Last Defense

The Last Defense

In the past two years, new words have crept into the vocabularies of Americans: West Nile Virus, SARS, Monkeypox. As people struggle to understand what happens when diseases jump from one continent to another, a University of Arkansas researcher and her colleagues are looking at the mechanisms that underlie the immune response to infection. Such an approach could lead to a more universal way of fighting emerging diseases.

When Tammy Kautzer purchased two small prairie dogs at a 4-H pet exchange in Wausau, Wisc., on Mother’s Day, she had no idea that her life would soon be linked to a little-known country in Africa.

She brought the two tiny mammals to her home in Dorchester, Wisc., and introduced them to her 3-year-old daughter, Schyan. Two days later, one of the animals appeared to be sick. Schyan tried to play with the animal, and her mother told her to put it back in its pen. When Schyan was putting it away, the prairie dog bit her on the finger.

All the devastation caused by the wars and weapons of the 20th century — the nuclear war heads, the mines, the tanks and machine guns — pale in the face of the world’s most pervasive killers. Unseen, they invade by stealth and kill from within. The names of some of these threats caused the most robust people to tremble in the early 1900s — smallpox, diphtheria, polio. And influenza in 1918 wiped out millions of people world-wide.

With the advent of vaccines in the 1950s and 60s, many researchers thought humans might win the war against microbes. Indeed, the year 1977 marked the last case of smallpox seen in the world. To most Americans, influenza seems more an inconvenience than a major threat. And we have vaccines that protect against diphtheria, polio and other diseases that once plagued humans.

Yet even as certain viruses and bacteria retreat, others have moved forward to take their places, and they have taken on equally ominous forms. Human immunodeficiency virus, which causes AIDS, emerged in the 1980s. The Ebola virus made a gruesome debut in Africa in the 1990s. Monkeypox and West Nile Virus, once native to Africa, have jumped continents to become a world-wide problem. And a new pathogen that causes Sudden Acute Respiratory Syndrome (SARS) has emerged, spreading rapidly from person to person seemingly by close proximity to someone with the disease.

Traditional vaccines rely on the body’s recognition of and response to a pathogen. When foreign microorganisms enter the body, the immune system sets to work to disable or destroy them. The immune system produces both antibodies and cells that bind to the microorganisms and shut them down. After the invasion is turned back, a few cells that “remember” the microorganism remain, in case of another incursion. These memory cells create a faster response if the pathogen tries to invade again, often preventing illness before it begins.

Traditional vaccines use killed disease-causing organisms, parts of organisms, weakened organisms or low-level toxins to induce immune responses specific to particular diseases. This, in turn, boosts the immune system’s memory of this particular disease-causing microbe, so that if it tries to invade the body again it is quickly vanquished. Unfortunately, immunity produced by these non-threatening traditional vaccines is weak.

Today’s researchers continue to seek ways to make new vaccines specific to various organisms, but University of Arkansas professor Jeannine Durdik has taken a different path. She’s examining the basic mechanisms the immune system uses to fight disease in hopes of finding a universal pathway that might be used as the basis of making the specific vaccines better and stronger than they are in their current forms.

At first Schyan Kautzer’s bite swelled and reddened a little, but it didn’t seem unusual. However, by the next weekend Schyan had a fever that wouldn’t abate. On Monday the Kautzers took their daughter to a doctor at the Marshfield Clinic, and while they were there had him look at the bite. He immediately referred them to Kurt Reed, an infectious disease pathology specialist and director of the clinical research center at the Marshfield Clinic Research Foundation.

Schyan developed red spots on her body. Her fever shot up to 104 degrees, and she refused to eat or drink. The physicians hospitalized her, put her on an IV, gave her antibiotics and began to run some tests. The day Schyan entered the hospital, the sick prairie dog died.

“For the first three days she just lay there, mostly sleeping, crying when she woke up,” said Kautzer. “Then she woke up and said, ‘Mommy, did I die?’ And I just cried.”

The doctors took a biopsy of the tissue from the red spots, but it did not test positive for cowpox or herpes virus, two of their first guesses. Three days into Schyan’s hospitalization, she wasn’t responding to antibiotics, and they still didn’t know what was wrong. Then her mother started to get itchy red spots on her body.

Durdik and her colleagues have started to examine immune memory in an attempt to understand how it works within the immune system. Durdik and her colleague, Satyajit Rath of the National Institute of Immunology in Delhi, India, wanted to look at ways to enhance immune system memory that may potentially augment the effectiveness of vaccines.

A teaspoon of blood contains perhaps a million lymphocytes, cells that help kill or disable illness-causing pathogens. Of these million lymphocytes, perhaps 10 recognize a particular pathogen. In sheer numbers, a flu virus or pneumonia bacterium could easily overwhelm the lymphocytes, but when they recognize the enemy, the lymphocyte cells multiply by dividing, creating huge numbers of cells specific to warding off the invading pathogen.

However, once the intruders have been shown the door, the lymphatic system needs room for other types of cells to remain vigilant for all types of diseases. So most of the cells specific to the pathogen must die. The rise and fall of these cells occurs almost simultaneously.

The cells that don’t die — the ones left behind when the infection recedes — confer immune memory in the body. If the same pathogen invades the body again, these cells will rise up and stop it before another infection can begin.

Up to now, vaccines have operated on the premise of stimulating the immune system memory by exposing the lymphocytes to a small part of the pathogen. But Durdik and Rath want to look at the cell build up and death to see if control at the immune system level is possible.

“If we can control cell death so it goes from 100 to five instead of 100 to one, we have a five-fold increase in memory,” Rath said.

One of the molecular players in cell death turns out to be a drug commonly used to thin blood. They measured the immune response in chickens that received the drug with the vaccine and those that didn’t, and found that the drug-enhanced animals had a higher level of immune response than the ones who just received the vaccine.

“With one week of treatment, long-term persistence of immune memory is significantly improved months later,” Durdik said.

In addition, the nature of the drug has led Durdik and Rath to other ideas on how the cell death pathway is controlled. They are now looking at common signaling molecules like nitric oxide, which plays a major role in controlling dieback or expansion of immune cells and in determining the amount of memory that persists.

Tammy Kautzer’s illness progressed from bumps to cold sweats at night.

“I couldn’t stay warm enough, and yet I was drenched,” she said. Her glands swelled to the point where it hurt to swallow. A few days later, her husband also developed symptoms.

“You felt like you had the flu,” she said.

Schyan spent a total of seven days in the hospital. She didn’t respond to several different types of antibiotics, but Kautzer finally noticed that one eye, which was swollen shut, seemed to be improving. The Kautzers took their daughter home and felt better in a little under a week.

The day after Schyan left the hospital, a biopsy from Tammy Kautzer detected an orthopox virus — monkeypox, a disease formerly found only in Africa.

The news exploded on the national scene as the Centers for Disease Control and Prevention and other government organizations attempted to trace the origins of the microbe. They traced it from the infected prairie dogs bought at a swap meet to SK Exotics of South Milwaukee, then to a wildlife importer in Texas. The prairie dogs were housed with a Gambian rat, three dormice and two rope squirrels that were shipped from Ghana on April 8.

As people grow older, they seem to lose the protection that the immune system afforded them when they were younger. Indeed, studies have shown that most vaccines do not work on the elderly, and that vaccine-induced immunity can wear off as people grow older. So it seems that older people stop maintaining immune memory, and Durdik and Rath ask the question: Why?

To answer this question, Durdik turned to mice, because mice age rapidly, becoming old at about 16 months.

She looked at cell explosion and cell death by taking young and aged mouse T-lymphocytes and exposing them to a trigger that causes the lymphocytes to multiply and then die. She then took samples of the cells at 10, 20, 30 and 40 hours and examined the samples for differences.

Durdik and Rath used a flow cytometer to track dividing cells. All of the original sample cell proteins are marked with fluorescent markers, then the cells are sent in a continuous stream through a laser beam that marks their journey. As the cells divide to create new generations, the new proteins made do not fluoresce. These proteins dilute the old ones. As the cells divide, the next generation is half as bright as the previous generation, and this can be translated into a measurement of new cell growth.

The researchers can follow cell division for about seven generations. Durdik creates contour plots that show how the cells proliferate over time.

“Expansion upon stimulation does not appear to be dramatically different between young and aged cells,” she said.

However, the story changes when it comes to cell death.

Immunologists know that a normal cell won’t let much through its membrane.

“It’s an excellent barricade,” Rath said.

When cells die their membranes become leaky. So the researchers added a fluorescent dye that brightens when it comes in contact with DNA. This second dimension of fluorescence tracks the “dead guys,” Durdik said.

The contour plot of cell death clearly shows that lymphocytes die off more swiftly and completely in aged cells than in young cells. Like a person who can’t remember what the car keys are for, the aged immune system appears to lose the ability to retain the memory of past bacteriological and viral insults.

The next step in Durdik’s lab will be to look closely at the cell death patterns to determine why this mechanism changes between youth and age. The answer may provide a new way to boost the immune system and keep it safe from the perils that beset it daily.

The Kautzers represent three people sickened in an outbreak that infected 79 people with a virus previously unseen in the United States. Their story shows how diseases once indigenous to isolated parts of the world can now travel globally, how a rodent from a remote region of Ghana in Africa can affect the life of a three-year-old girl and her family in Wisconsin.

Monkeypox has no cure, and no vaccine specific to its prevention. In Africa, the virus kills one to 10 percent of people who contract it. Its sudden emergence on the North American continent illustrates how ill prepared we are as a global community to deal with the consequences of a microbiological invasion.

Durdik’s research will not create immediate solutions to this problem. However, her research provides a fundamental backdrop for addressing concerns about emerging infectious diseases in a more universal way than through traditional vaccines.

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