May 7, 1998 The gene mutation that causes cystic fibrosis also appears to protect against infection with typhoid fever bacteria, a study supported by the National Institute of Allergy and Infectious Diseases (NIAID) has found. The finding could explain why an estimated 12 million people in the United States carry the gene for such a highly fatal childhood disease. Researchers led by Gerald Pier, Ph.D., of Brigham and Women's Hospital and Harvard Medical School in Boston, report the finding in the May 7, 1998, issue of the journal Nature.
"This is an interesting finding that underscores how basic research in one disease area often leads to discoveries in another area," says NIAID Director Anthony S. Fauci, M.D. "It also is a good example of how pathogenesis research - the study of how pathogens interact with the host to cause disease - creates opportunities for applied research."
Approximately 2,500 babies with cystic fibrosis are born each year in the United States. Before the 1950s, most children with the disease died by age 1 or 2. Today, with better methods for managing the disease, the average survival of these individuals is about 30 years.
"In most cases of inherited disease with high rates of childhood mortality, the defective gene does not remain in the gene pool," says Dr. Pier. "The disease and the gene causing it literally die out. When that doesn't happen, we find that it is because carriers - healthy people with one good copy and one bad copy of the disease gene - have some enhanced survival advantage." For example, Dr. Pier notes that individuals with a single copy of the sickle cell disease gene are more resistant to malaria infection than people who do not have the gene.
Scientists have speculated that cystic fibrosis carriers also have enhanced protection against an infectious agent, but until now, they didn't know which one.
Cystic fibrosis develops in children who inherit two mutant copies - one from each parent - of the gene that encodes a protein known as cystic fibrosis transmembrane conductance regulator (CFTR). In these children, abnormal CFTR blocks the movement of chloride ions and water in the lungs, gastrointestinal tract, and other tissues and causes them to secrete large amounts of mucus. As mucus accumulates in their lungs, these children become increasingly susceptible to life-threatening respiratory infections.
Infection with Pseudomonas aeruginosa is one of the primary clinical features of cystic fibrosis. Last year, Dr. Pier and his colleagues reported that the normal CFTR protein acts as a receptor for P. aeruginosa and helps clear this bacterium from the lung. When CFTR protein is abnormal or missing, it does not bind and ingest this bacterium, and lifelong infections are thus established in many individuals with cystic fibrosis.
The researchers hypothesized that other bacteria might interact with CFTR in a similar manner. Finding no other lung pathogens that use the CFTR entry pathway, Dr. Pier and his colleagues turned their attention to the gastrointestinal tract, since its tissues also are affected directly in people with cystic fibrosis.
Dr. Pier and his colleagues showed that normal CFTR protein also acts as a receptor for Salmonella typhi, the gastrointestinal pathogen that causes typhoid fever. In tissue culture experiments, they found that human cells expressing normal CFTR took up significantly more S. typhi than did cells expressing mutant CFTR. The researchers then added to the cells antibodies and synthetic molecules designed to bind to a segment of the CFTR molecule that protrudes from the cell membrane. These agents blocked the uptake of S. typhi by CFTR, thus identifying the protruding CFTR segment as the S. typhi binding site through which it enters cells.
"Uptake and ingestion of S. typhi by epithelial cells is part of the body's normal protective response," explains Dr. Pier. "Epithelial cells ingest the bacterium, then slough off of the epithelial surface. New epithelial cells soon take their place. At low concentrations of S. typhi, this process prevents infection. High concentrations, however, can overwhelm this protective response. After S. typhi-ingesting epithelial cells have been shed from the epithelial surface, any excess S. typhi are free to attack the underlying tissue, which lacks this defense mechanism."
Since abnormal CFTR binds poorly to S. typhi, cystic fibrosis gene carriers would be protected from this infectious process and thus spared the high mortality associated with typhoid fever. Dr. Pier notes that before 1900, typhoid fever was a major infectious disease in the United States that killed about 15 percent of infected individuals. It remains a serious problem in countries that lack adequate sewage treatment facilities, since contaminated water is a major source of S. typhi transmission.
Dr. Pier speculates that, in addition to advancing the understanding of how pathogens interact with host tissues to cause disease, this finding could have relevant applications in vaccine research, particularly in ongoing efforts to develop S. typhi-based vaccine delivery vehicles.
S. typhi stripped of its ability to cause disease is an attractive tool for vaccine researchers. Vaccines based on this gastrointestinal pathogen would be delivered orally, and thus might be useful for stimulating immunity at the mucosal surfaces that line the stomach and gut. AIDS researchers supported by NIAID recently initiated a clinical trial of an experimental vaccine composed of a weakened form of S. typhi into which a gene for a human immunodeficiency virus (HIV) protein had been inserted.
"Our work provides an understanding of how S. typhi gets into the tissues of the host's immune system," says Dr. Pier. "By manipulating S. typhi or other organisms to deliver antigens via the CFTR-uptake pathway, we may be able to develop better vaccines." In future studies, he and his colleagues will try to define the S. typhi surface molecules that bind to CFTR. "It may be possible to use this structure to make non-living antigen delivery vehicles that target antigens to the immune system following oral ingestion."
NIAID supports research on AIDS, tuberculosis, malaria and other infectious diseases, as well as allergies and immunology. In addition to NIAID, the National Heart, Lung and Blood Institute (NHLBI) supports Dr. Pier's current research. NIAID and NHLBI are components of the National Institutes of Health (NIH). NIH is an agency of the U.S. Department of Health and Human Services. ###
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