Respiratory illnesses like pneumonia and bronchitis are so common and widespread, you might think doctors had pinned down all of their causes by now. But surprisingly, until the early 1980s, no one knew that at least 10% of pneumonia cases and perhaps 5% of bronchitis and sinusitis cases are caused by a microorganism now called Chlamydia pneumoniae.
Catching and identifying this bug was accomplished through a combination of a bit of serendipity and considerable detective work on the part of UW epidemiology professor J. Thomas Grayston and professors San-Pin Wang, C. C. Kuo, and Lee Ann Campbell of the UW pathobiology department. Their achievements are important in two major respects. Besides finding a totally new bacterial cause of human respiratory disease, and describing its epidemiological and clinical characteristics, Grayston has gone on to study the unexpected relationship of this organism to heart and blood vessel disease.
The story of C. pneumoniae's discovery began in 1965 in Taiwan. Grayston and colleagues had been studying the eye disease trachoma, and were conducting trachoma vaccine trials there. They isolated the prototype strain during that year from the eye of a child participating in the vaccine study. It was the 183rd isolation that they had made in their studies of the eye disease, and they assumed it was similar to the other isolates, all of which were known to be the organism Chlamydia trachomatis, commonly--and inaccurately--called the trachoma virus at that time. These organisms now are classified as bacteria which grow only intracellularly. Trachoma is still the world's leading infectious cause of blindness. More importantly for the U.S., Chlamydia trachomatis is a major cause of genital tract infections and sterility.
By 1970, new cell culture techniques led the researchers to realize that the TW-183 isolate was different from the others; they assumed it was a Chlamydia psittaci, the only other species of chlamydia then known. The blood test for chlamydia developed in Grayston's laboratories in 1972 led the researchers to determine that this "orphan strain," isolate TW-183, was not associated with eye disease; however, antibodies against it were very common in the general population. It wasn't until the early 1980s that an accidental finding led the researchers to realize that this orphan strain was actually associated with acute respiratory infection.
This serendipitous discovery came about when the TW-183 strain was used as a control in a study looking for evidence of C. trachomatis-caused respiratory infections in adults. (That microorganism was known to cause such infections in infants.) A control, by definition, was not supposed to cause any reaction; but the supposed "control" strain TW-183 reacted in tests involving patients with pneumonia!
With that observation, Grayston finally had the first major clue about the significance of the orphan strain that he had found so many years before. Shortly thereafter, he succeeded in cultivating microorganisms identical to TW-183 from UW students with acute respiratory disease. And by 1989, Grayston's team established these new isolates as a separate species of chlamydia which they named Chlamydia pneumoniae after the disease most commonly associated with it. The work of many laboratories around the world subsequently confirmed the findings.
"The second part of the story and the part that now occupies our major interest is an association between Chlamydia pneumoniae and atherosclerosis," says Grayston. Finnish researcher Pekka Saikku, who had trained in Grayston's lab at the time that they were discovering the significance of the TW-183 strain, reported a surprising finding from a study in Helsinki. Saikku noticed that patients with coronary artery disease or myocardial infarction had more antibody against Chlamydia pneumoniae than did controls in the general population. Subsequent studies by both the Finnish and UW groups confirmed the association, and several other labs from around the world have reported similar findings.
Important additional evidence for an association between Chlamydia pneumoniae and atherosclerosis comes from the direct demonstration of the organism in the diseased artery. The researchers used a battery of different techniques, including electron microscopy and the most modern tools of molecular biology, to determine that Chlamydia pneumoniae is indeed present in the majority of atherosclerotic plaques, the lesions of arterial disease. Furthermore, they showed that the microorganism is more commonly found in cardiovascular tissue than in lung, liver, spleen, lymph node, or bone marrow tissues, so there must be a special relationship between Chlamydia pneumoniae and cardiovascular tissue.
Grayston feels the data on the association are solid, but, he notes, they don't actually prove a causal relationship—something always difficult to do in science. "It is possible that the organism could play a role in the initiation of the disease," he notes, referring to the "response to injury" hypothesis (see Getting to the Heart of Atherosclerosis), or a role in promoting the growth and severity of the disease.
Meanwhile, skepticism remains. "Our situation is somewhat similar to that of the investigators of Helicobacter pylori, who were faced with great skepticism concerning the role that microorganism played in ulcers of the stomach and duodenum," observes Grayston. Only recently has it been widely recognized that a bacterial infection can cause ulcers, which can be effectively treated with antibiotics, not antacids.
"We are following two approaches to try to understand the role of Chlamydia pneumoniae in atherosclerosis," says Grayston. "One is to study animal models, and the other is human treatment trials. We now have some initial success in the use of a mouse model of atherosclerosis. We have found that Chlamydia pneumoniae infects this mouse, and that the organism can be recovered, not only from the lung, but from the aorta, for many months after the infection. And we are also attempting to organize human treatment trials."