Studies Widen Role of Germs in Disease

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Studies Widen Role of Germs in Disease

By Rick Weiss
Washington Post Staff Writer
Monday, March 1, 1999; Page A1

From gallstones to arthritis to heart disease, many illnesses long presumed to have roots in genes or lifestyle may be caused largely by infectious agents, a growing number of scientists believe. That prospect is raising the intriguing possibility that people can "catch" kidney stones, cerebral palsy or Alzheimer's disease.

Most of the evidence remains circumstantial. A microbe may be suspiciously present in people who have a disease, for example, and not in those who don't – suggesting, but not proving, causality.

But for some conditions – including heart disease, the nation's top killer – many scientists feel certain that microbes play at least a contributing role where none was suspected previously. Last week, researchers announced that they had discovered a molecular mechanism by which mice can get heart disease from a bacterium. And high-tech tests have been picking up previously undetectable bacterial "fingerprints" in people with other chronic conditions, strengthening the case that microbes are the hidden perpetrators in those diseases as well.

The implications of the new theory are enormous, researchers say. Most important, it suggests that vaccines or antibiotics may have an unexpectedly big role to play in the treatment of chronic diseases that today are treated with only modest success through lifestyle changes, such as exercise and improved diet.

"If an infectious agent is responsible for even a portion of these diseases, that could change the outlook for treatment and prevention dramatically," said Barry Bloom, dean of the Harvard School of Public Health. "I see chronic disease as the next frontier for vaccines."

Bloom and others cautioned against placing too much blame on bacteria. For most chronic diseases, they are probably just part of the puzzle, they said. And the prospect of widespread, long-term use of powerful antibiotics carries its own problems, including the possible emergence of drug-resistant "superbugs." Attractive though the idea may be, a pill or shot will not likely allow people to ignore everything they have learned about how to remain healthy into old age.

"The bacteria by themselves are not going to give us the only useful answers," said Janice Kiecolt-Glaser of Ohio State University, who studies the effects of stress on health. "You could have the bug, and if resistance is altered by stress or other factors, you could be more prone to not healing or to the infection progressing."

Nonetheless, said Anne Schuchat, chief of the respiratory diseases branch at the Centers for Disease Control and Prevention (CDC) in Atlanta, chronic conditions such as heart disease take such a big toll on society that even a modest contribution by bacteria deserves to be targeted. "Even if there are still a lot of questions," she said, "it's really worth a lot of attention."

The revolution began about five years ago, when definitive evidence arose that stomach ulcers are caused not by excess stomach acid, as had long been presumed, but by the bacterium Helicobacter pylori.

It wasn't easy persuading the scientific community to accept the new model. Barry Marshall, an Australian scientist with a flair for theatrics, resorted to swallowing a beaker of the bacteria to help settle the question. Today, ulcers are treated primarily with antibiotics instead of acid-blocking drugs.

Infectious disease specialists now are turning their attention to coronary artery disease, which is caused by a progressive buildup of fatty deposits inside vessels that feed the heart. Scientists have long known that diabetes, high blood pressure, tobacco use and a family history of the disease increase a person's odds of artery disease and the risk of a subsequent heart attack or stroke. But those factors account for only about half the incidence of this disease.

Several lines of research support the proposition that a microbe might cause coronary artery disease. In 1997, Boston researchers showed that men with higher levels of a certain protein circulating in their blood over a period of years had an increased risk of eventually suffering a heart attack or stroke. The protein is a well-known sign of inflammation, which can indicate a bacterial infection.

Separately, Joseph B. Muhlestein of the LDS Hospital in Salt Lake City and his colleagues discovered that a peculiar bacterium, Chlamydia pneumoniae, often can be found inside blood vessel cells of people with heart disease – but not generally in the cells of healthy people.

C. pneumoniae – a close cousin of C. trachomatis, which causes a common sexually transmitted disease – is best known as a cause of pneumonia and bronchitis. It is unlike most other bacteria because it lives not on cells but inside them, much as a virus does.

It is possible that the microbe is just an innocent bystander – a bacterium that feels at home in arteries damaged by years of hamburger consumption and a lack of exercise. But rabbits on fatty diets develop hardening of the arteries much faster when they are infected with C. pneumoniae, suggesting that the microbes actively contribute to the disease.

A study published in the journal Science last Friday offered the best evidence yet for precisely how chlamydia may cause heart disease. A protein found on chlamydia, it turns out, is almost identical to one found in heart tissue in mammals. Scientists discovered that when a mouse's immune system attacks the bug, it accidentally attacks the heart protein, too. The resulting syndrome is not exactly the same as human heart disease, said Josef M. Penninger, the University of Toronto immunologist who led the study. But the similarities have convinced him that something very much like this may be causing heart disease in people.

If Penninger is right, then heart disease might be prevented or even reversed by a drug that tempered the immune system's reaction to chlamydia. Scientists trying to create a vaccine against chlamydia would face a challenge, however. Vaccines work by stimulating the immune system and could inadvertently trigger the immune response that causes heart disease.

If the microbe, and not the immune response against it, causes heart disease directly then antibiotics might prove useful. Two studies in people have indicated that a short course of antibiotics known to kill chlamydia can reduce the risk of a heart attack or stroke for up to 18 months. Another study was unable to verify the benefit and other studies are ongoing.

Heart disease is not the only chronic disease in which C. pneumoniae may play a role. Neuroscientist Brian Balin of the Philadelphia College of Osteopathic Medicine and his colleagues have found signs of the microbe in 27 of 29 autopsied brains of people with Alzheimer's disease, but in only one of 19 brains from non-Alzheimer's patients.

The bacteria, found in so-called glial cells that surround neurons, may be "opportunists" taking advantage of dying brains, Balin said. But studies indicate that they can cause Alzheimer-like damage. "I think it's definitely an agent that has to be considered as a potential causative or at least a risk factor for Alzheimer's disease," he said.

Gallstones and kidney stones recently have been added to the list of diseases that might have microbiological roots. Studies led by Phillip B. Hylemon of the Medical College of Virginia in Richmond, for example, showed that gallstone patients have 100- to 1,000-fold higher levels of Clostridia and eubacteria in their intestines. Those bacteria generate deoxycholic acid, which prompts the liver to secrete bile especially rich in cholesterol – a key risk factor for gallstone formation. In one encouraging finding, antibiotics have been shown to lower the concentration of these bacteria in people and decrease bile levels to below the threshold needed to make gallstones.

Last summer, Finnish researchers reported provocative evidence that "nanobacteria" – smaller than many viruses – may be a cause of kidney stones. Using genetic fingerprinting tests and other methods, they found that the bacteria can build a mineralized coating around themselves, upon which additional proteins and minerals can accumulate. In one study of 30 kidney stones, all had traces of nanobacteria in their cores. DNA studies suggest that the nanobacteria are related to a small, slow-growing, rod-shaped bacteria known to cause abortions in animals and blood poisoning in people.

Juvenile rheumatoid arthritis, generally considered an immune system disorder, also may be caused by a microbe, although the evidence remains indirect. The proposed culprit is Mycoplasma pneumoniae, a common cause of "atypical pneumonia" in people. In a 17-year Canadian study, diagnoses of the disease peaked in the same years as M. pneumoniae infections did.

Some researchers suspect that scleroderma, a painful chronic disease affecting connective tissues under the skin, also may be caused by mycoplasma. A recent U.S. study found a virtually complete disappearance of symptoms in four of six patients treated for one year with an anti-mycoplasma antibiotic called minocycline.

Cerebral palsy, too, may prove to be infectious. That disease, which affects about 500,000 Americans and is characterized by brain damage at birth, was long believed to have been caused by oxygen deprivation before or during birth. But a study last year suggested that infected amniotic fluid may often be to blame.

Researchers have not isolated a particular microbe from newborns with cerebral palsy. But a technique being studied by David Relman at Stanford University may help scientists find the cause of that and other diseases for which there is evidence of infection but no isolated microbe. Relman is using DNA fingerprinting methods to find tiny fragments of microbial DNA in cells of people with various diseases.

Some scientists suspect that such tests will reveal infectious causes for more and more chronic diseases. "They will pop up in all kinds of places," the University of Toronto's Penninger said.

Attractive as the emerging evidence is, not everyone is so sure. To a microbiologist, the world can sometimes seem full of "infectious agents in search of a disease," said Schuchat of the CDC. "How much is real and how much is a fad remains to be seen."

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