The Infection-Chronic Disease Link Strengthens

Infection" is usually associated with an oozing sore, a bout with the flu, or an outbreak in some exotic place. But infectious organisms lie behind many chronic illnesses too, and an increasingly molecular approach to diagnosis is clarifying some of these relationships. An invited panel discussed "The Infectious Etiology of Chronic Diseases" at the second International Conference on Emerging Infectious Diseases, held in Atlanta July 16-19. Chronic diseases take a huge toll. "In the [United States], 70 percent of all deaths are due to one or more chronic diseases, and more than 90 million people suffer daily," said session opening speaker Tom Quinn of the laboratory of immunoregulation at the National Institute of Allergy and Infectious Diseases. Even diseases not typically associated with pathogens may have underlying infectious causes. "Of the eight million new cases of cancer in the world each year, a million are attributable to a known infectious agent," said Valerie Beral, the director of the Imperial Cancer Research Fund cancer epidemiology unit at Oxford, U.K.1 The infectious origins of some chronic illnesses have been known for decades. These include tuberculosis, syphilis, leprosy, and a number of parasitic diseases. "Only more recently have we been realizing that coronary artery disease, diabetes mellitus, cancer, and neurological disorders can have an infectious etiology, either as a cause or a cofactor," Quinn explained. Cancer led the way, added Beral. "Infection-cancer links were regarded as curiosities until after World War II, when interest in viruses and cancer began to accelerate. The 1960s saw a huge epidemic of discoveries on the role of viruses in cancer in animals," she said.2 Considering an infectious cause of a slowly manifesting disease requires reanalysis of Koch's postulates, which have guided microbiology since 1884. "Koch's postulates are relevant for acute infections, but we run into problems when we think about chronic or long-term symptoms," said Beral. According to these guidelines, to demonstrate infectivity, the suspected agent must be present in affected individuals but not in others; be isolated and grown in pure culture; cause the associated symptoms when inoculated into a healthy individual; and then be isolated from that individual. The first criterion remains--the microbial culprit must be present. But the requirements to culture microorganisms and demonstrate infectivity may have become obsolete. And the technology that has catalyzed this obsolescence is revealing new causes of disease too. That is, infection-chronic disease links may have been undetectable in times past simply because the tools of microbiology did not reveal all that was there. "Why are there unrecognized pathogens? Because of the completely unanticipated microbial diversity that was not known when we relied on culture-based methods," said Stanford University assistant professor of medicine David Relman. He is referring to the classification of prokaryotes based on ribosomal RNA sequences and other molecular characteristics. "Of the 36 divisions of microbial life, seven are known to include animal pathogens. We don't have a good handle yet on whether the other groups have pathogens," he added. No longer does diagnosis depend on a series of infections and nurturing of the pathogen--genes do the trick. "Sequence-based molecular methods can detect the pathogen or the host's response," said Relman. The trend to look for molecular signatures will grow as genomics, proteomics, and DNA microarray technology mature. Image: Courtesy of Ian LipkinA film sequence illustrates complex, repetitive behaviors in a rat infected with Borna disease virus, as well as one engaged in self mutilation. On the Matter of Mechanism Microbes don't use one single strategy to disable their hosts for the long term. The route may be to turn the victim against itself, as in the classic attack of autoantibodies "mistaking" heart valve cells for Streptococcus. Persistence or repeated infection may wear down or irritate a body part, such as HIV's assault on the immune system or Chlamydia's association with pelvic inflammatory disease. Nor is the infection connection necessarily obvious or direct, as Helicobacter pylori illustrates.3 H. pylori's association with gastritis and peptic ulcers revolutionized their treatments, replacing bland diets with antibiotics. The microbe lives in the gastric mucosa, where it secretes urease, which breaks urea down into carbon dioxide and ammonia, resulting in a cloud that protects the pathogen from the ravages of stomach acid. H. pylori's role in causing stomach cancer is somewhat more circuitous. "H. pylori infection causes chronic inflammation in the stomach, which leads to increased antioxidant consumption, which in turn leads to increased cell proliferation. At the same time, DNA repair declines and DNA damage increases. The result can be mutation that leads to cancer. It is the same mechanism as for all inflammation-related cancers. This is indirect, caused by the host response to an infectious agent," explained Julie Parsonnet, an associate professor of medicine at Stanford University. Here, too, DNA microarrays to reveal host genotypes that set the stage for H. pylori infection will help clarify the picture. "Half of the people worldwide are infected with H. pylori, but less than 1 percent get this cancer. Why?" Parsonnet asked. She described Napoleon Bonaparte's family, in which genetic susceptibility may have contributed to several cases of a gastric cancer that may have been bacterial in origin. Linking Chlamydia and Atherosclerosis The H. pylori-ulcer association was clearly established before the mechanism was unraveled. This is apparently also the case for an emerging link between Chlamydia pneumoniae infection and cardiovascular disease. The bacteria cause a common respiratory infection. The first tentative links came from Chlamydia detected in plaque in coronary blood vessels removed during transplants in the late 1980s, said Quinn. In 1998, researchers used stored blood samples to show that antibodies to Chlamydia were associated with a 10-fold increased incidence of bacteria present in atherosclerotic plaque among a group of Alaskans who had died in accidents.4 Experiments in pigs, rabbits, and mice also revealed a Chlamydia-atherosclerosis connection. More recently, the Northern Manhattan Stroke Study found that people infected with the bacteria are 4.5 times more likely to have had a stroke than matched controls who show no evidence of having encountered the microbe.5 Two pilot studies suggesting that antibiotics could treat heart disease led to the ongoing Azithromycin and Coronary Event Study clinical trials supported by the National Heart, Lung and Blood Institute and involving 4,000 patients in 26 medical centers. The trial will investigate whether the antibiotic azithromycin (Zithromax, Pfizer Inc., Groton, Conn.) taken weekly in addition to standard treatments for cardiovascular disease can lower the risk of stroke and heart attack over the next three years. Borna Disease Virus and Behavior Chlamydia pneumoniae is a fairly familiar microorganism. Ian Lipkin, Louise Turner Arnold Chair of Neurosciences, and his colleagues in the emerging diseases laboratory at the University of California, Irvine, investigate the less well-known Borna disease virus. The virus causes behavioral disorders in a variety of vertebrates and, Lipkin hypothesizes, could could serve as a model to investigate such conditions in humans as schizophrenia, autism, panic disorder, chronic fatigue syndrome, and bipolar disorder. Experiments reveal that the virus infects cells of the limbic system and dopamine circuits. At the meeting, Lipkin described the aberrant behavior of infected rats, the work of assistant professors Marylou Solbrig and Mady Hornig. "First, the virus inhibits exploratory behavior. Then the animals become hyperactive, carrying their petri dishes from one side of the cage to another, and mutilate their tails." With a device used to detect bat sonar, the researchers found that infected pups cannot communicate normally, perhaps similar to autistic humans. Associated brain abnormalities include malfunction in the hippocampus, which controls learning and memory; a loss of Purkinje cells in the cerebellum, which affects coordination; and a change in the distribution of excitatory amino acids. In another set of experiments in the Irvine lab, mice infected with the virus display behavior reminiscent of obsessive-compulsive disorder. Borna disease virus research may provide new animal models of human behavioral disorders as well as explain how some of them may arise. Establishing infection-chronic disease connections is an epidemiological goal with tangible applications. Summed up the last speaker, Gail Cassell, a research scientist at Eli Lilly and Co. in Indianapolis, on the value of identifying infectious causes of chronic diseases, "It is important to try to do this because many infectious agents are commonly transmitted and treatable with existing antibiotics or antivirals, or preventable by vaccines. We have a lot to learn about how organisms live in the human body and subvert the immune response." Ricki Lewis (rickilewis@nasw.org) is a contributing editor for The Scientist. References 1. E. Russo, "Cancer and viruses," The Scientist, 14[4]:10, Feb. 21, 2000. 2. D. Steinberg, "Virus-disease links are hard to forge," The Scientist, 14[8]:8, April 17, 2000. 3. J.R. Warren and B. Marshall, "Unidentified curved bacilli on gastric epithelium in active chronic gastritis," Lancet, 1:1273-5, 1983. 4. M. Davidson et al., "Confirmed previous infection with Chlamydia pneumoniae (TWAR) and its presence in early coronary atherosclerosis," Circulation, 98:628-33, 1998. 5. M.S.V. Elkind et al., "Chlamydia pneumoniae and the risk of first ischemic stroke," Stroke, 31:1521, July 2000.

The Infection-Chronic Disease Link Strengthens

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