We're all taught from childhood that "every cloud has a silver lining."

One manifestation of this anecdotal finding is the strange-bedfellow fact that people born with one defective gene for sickle-cell anemia enjoy built-in protection against malaria. In parts of Africa and Asia, where malaria is endemic, large segments of the population are heterozygous for the aberrant hemoglobin gene that inflicts sickling.

Now, a second documented example of such linkage between discordant diseases has surfaced. It's implied by the title of an article in today's Nature, dated May 7, 1998: "Salmonella typhi uses CFTR to enter intestinal epithelial cells."

That paper's lead author, Gerald Pier, is a microbiologist and immunologist at the Harvard-affiliated Brigham and Women's Hospital, in Boston. "Our overall finding," he told BioWorld Today, "is that the reason cystic fibrosis [CF] is so common in European populations, and populations of European descent, is that the carriers of the defective gene for CF have increased resistance to typhoid fever."

CF is the most common inherited disease among Caucasians of European ancestry. Its cause is a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR), bequeathed to a CF child by both its carrier parents. This genetic mishap brings some 2,500 CF babies a year into the world in the U.S. alone.

Until the 1950s, most such homozygous infants died before their second birthdays. Nowadays, thanks to improved medical care, especially antibiotics, they live into their 30's.

These CF victims die for the most part of chronic lung infection, brought on by a ubiquitous bacterium Pseudomonas aeruginosa, which targets their lungs by preference. (See BioWorld Today, April 10, 1998, p. 1.)

Pier and his colleagues reported last year that in healthy people, with intact CFTR genes expressing normal CFTR, that protein acts as a receptor for P. aeruginosa, and helps clear the bacterium from the lung. CF patients lack this pulmonary protection.

"When we looked for other bacteria that infect the CF lung," Pier recounted, "we couldn't find any. But CF also affects the gastrointestinal tract, where GI complications are pretty well managed clinically."

Looking for possible interactions with gut pathogens, he and his co-authors came upon Salmonella typhi, the typhoid-fever bacterium. "As we investigated it further," Pier went on, "we realized it may have implications for the so-called heterozygous carrier advantage hypothesis — like sickle cell and malaria."

Typhoid's Delivery Vehicle: Dirty Water

Before 1900, typhoid fever was a major infectious disease that killed 15 percent of those who caught it. As recently as 1966, the Centers for Disease Control included it in a list of diseases almost eradicated in the U.S.

"Obviously, in the developed world," Pier pointed out, "where water supplies are kept pretty healthy, it's not a major problem. But it's not zero. There are outbreaks of typhoid when water gets contaminated. So it's still a major disease these days in areas of the world that don't have good public-health measures. Mostly, it's kids who die from it. Like malaria, If you get typhoid and survive, you develop immunity."

The experiments reported in Nature, Pier recounted, "began with a series of cells from a cystic fibrosis patient, cultured in our lab."

He and his co-authors bred transgenic mice that had either two good copies of the CFTR gene (wild type), or one CF-mutant bad one (heterozygous) or two bad ones (homozygous). Their results showed that the heterozygous carriers were much the least susceptible to infection with S. typhi. They racked up an almost 86 percent decrease in the number of bacteria that could invade their intestinal wall, compared to wild type mice. And in homozygous models, the typhoid bacterium had no ability to get from the gut's interior space into the intestinal wall, which it had to do in order to infect.

From these findings, Pier was able to narrate the events in the gut leading to the translocation, or invasion, of S. typhi into the submucosa:

Gut Cells Give Bacteria The Brush-Off

* "First, the typhoid bacillus binds to the intact CFTR protein in the gut. That causes the intestinal epithelial cells to ingest the organism. We believe that what happens next is that epithelial cells try to get rid of the bacteria, initially by shedding them from their surface.

* "When that happens with a low dose of the typhoid microbe, it's actually a protective mechanism for the healthy person. But if he or she swallows a high dose of S. typhi — around 10,000 to 100,000 organisms — the epithelial cells can ingest only some of those, in an attempt to clear them out.

* "This leaves a denuded or exposed basement membrane underneath that surface. We believe that the bacteria those epithelial cells fail to ingest take advantage of that naked or damaged epithelium, and invade through it into the submucosa below.

* "That lymphoid tissue is very rich in macrophages, into which S. typhi will go, where it can initially survive and replicate.

* "Eventually it will get out of those gut cells, and into the blood, where it causes typhoid fever, which is simply a bloodstream infection."

Pier noted that "right now there is an oral vaccine against typhoid fever, which is about 70 percent effective. It's used in many — but by no means all — parts of the world that need it.

"Our work," he continued, "gives an indication of a very important part of how that vaccine works to get the bacteria into the immune system's lymphoid tissues. We're working now to improve that vaccine, to target it to intestinal tissue where it can provoke an immune response."

Besides typhoid, Pier continued, "using weakened strains of S. typhi as an oral vaccine is actually a major area of research." For example, the NIH recently started a clinical trial employing attenuated S. typhi to deliver HIV antigens to prevent infection with the AIDS virus. (See BioWorld Today, April 17, 1998, p. 1.) *