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A Silver Lining for Cystic Fibrosis?

The mutation that causes cystic fibrosis may actually serve a useful purpose: protecting against typhoid fever. The finding, reported in tomorrow's issue of Nature, may help explain why this invariably fatal inherited disease is so prevalent today.

About one in 20 white Americans carry a defective copy of the gene for cystic fibrosis (CF), a disease whose hallmark symptom is thick mucous congestion in the lungs. Although people with only one bad copy of the gene are healthy, those who inherit two develop the disease. Before this century, CF was almost invariably fatal in childhood. Now, most victims live into their 20s, their most common cause of death being lung infections caused by bacteria such as Pseudomonas.

Healthy people can usually fight off a Pseudomonas infection, says Harvard University immunologist Gerald Pier, because the CFTR protein encoded by CF gene binds to the bug, bringing it into lung cells that can slay it. The same thing happens in the lining of the intestine when CFTR encounters Salmonella typhi. But there the strategy backfires: If S. typhi is pulled into intestinal cells, it causes typhoid fever.

Paradoxically, the defective CFTR that allows Pseudomonas to accumulate in the lungs of CF carriers may protect them from typhoid fever. When Pier exposed mice with defective CFTR to S. typhi, less than a tenth as many bacteria entered the intestinal cells--presumably because they couldn't bind to the altered CFTR. If the same phenomenon holds true in people, Pier believes, it would have given people with one defective CF gene an evolutionary advantage: They would have been more resistant to typhoid fever than normal people, without having cystic fibrosis.

Other experts say it's too early to come to that conclusion. "People have got to stop saying, 'I have found THE explanation for cystic fibrosis,' " says infectious-disease specialist Alice Prince of Columbia University. "It's more complicated than that." In 1993, for example, a similar link was proposed between cystic fibrosis and cholera. Prince believes it is possible that the CF mutation improved resistance to a wide range of diarrheal diseases, which used to kill far more infants than cystic fibrosis did.