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Secret Agent O157: The Evolution of a Killer


cover of Secret Agents: The Menace of Emerging Infections Every pathogen has a story, but the biography of E. coli O157:H7 is especially instructive because it shows how chance favors the prepared germ -- and how we are giving certain disease-causing organisms more chances than a rigged roulette wheel. Though E. coli O157:H7 has turned up in unpasteurized apple cider in 1991, 1996, and nearly every year since the Odwalla outbreak [in 1996], it is best known as the agent behind "hamburger disease." Hamburgers, in fact, are Rolls-Royce conveyances for O157. Think of your next Big Mac as the end product of a vast on-the-hoof assembly line. The story begins on hundreds of feedlots in different states and foreign countries. The animals are shuttled to slaughterhouses, where they become carcasses. The carcasses go to plants that separate meat from bone. The boning plants ship giant bins of meat to hamburger-making plants. The hamburger-making plants combine meat from many different bins to make raw hamburgers. At this point, your burger is more fluid than solid, because ground beef continually mixes and flows as it's made, its original ingredients indistinguishable. Grinding also multiplies surface area, so that the meat becomes a kind of soup or lab medium for bacteria. Finally, from the hamburger-making plants, these mongrel patties are frozen and sent to restaurants. A single patty may mingle the meat of a hundred different animals from four different countries. Or, looked at from another perspective, a single contaminated carcass shredded for hamburger can pollute eight tons of finished ground beef. Finding the source of contamination becomes impossibly daunting. (Making juice is also like making hamburgers: one bad apple can ruin a huge batch.) In the Jack in the Box outbreak, investigators found that the ground beef from the most likely supplier contained meat from 443 different cattle that had come from farms and auction in six states via five slaughterhouses. As the meat industry consolidates and the size of ground beef lots grows, a single carcass may have even more deadly potential. In 1997, Hudson Foods was forced to recall 25 million pounds of ground beef for this very reason: a small part of one day's contaminated beef lot was mistakenly mixed with the next day's, vastly spreading the risk.

E. coli O157:H7, the organism that this endless mixing amplifies, is a quiet tenant in the intestines of the 50 percent or so of feedlot cattle it infects, but a vicious hooligan in the human gut. In the bowel, Escherichia coli, rod-shaped bacteria first described by German pediatrician Theodore Escherich in 1885, perform a vital task by keeping disease-causing bacteria from taking over. For many decades, that knowledge obscured the fact that some forms of E. coli trigger violent disease. E. coli O157:H7 (the letters and numbers refer to immune system-provoking antigens on the body and on the whiplike flagella of the organism) was discovered in 1982, during an epidemic spread by undercooked patties from McDonald's restaurants in Oregon and Michigan. The outbreak wasn't highly publicized; even some scientists perceived O157 as more of an academic curiosity than a harbinger of bad things. Eleven years later, the Jack in the Box hamburger chain promoted its "Monster Burgers" with the tag line: "So good it's scary." These large, too-lightly-grilled patties killed four children and sickened more than 700 people -- bringing the exotic-sounding bacterium out of the lab and into public consciousness. In fact, however, by the time of the Jack in the Box tragedy, 22 outbreaks of E. coli O157:H7, killing 35 people, had already been documented in the United States. Suddenly, fast food hamburgers -- a staple of American culture -- were potentially lethal.

What makes E. coli O157:H7 so fearsome is the poison it churns out -- the third most deadly bacterial toxin, after those causing tetanus and botulism. Known as a Shiga toxin, because it is virtually identical to the toxin produced by Shigella dysenteriae type 1, it is a major killer in developing nations. The distinctive symptoms of E. coli O157:H7 are bloody diarrhea and fierce abdominal cramps; many victims say it's the worst pain they ever suffered, comparing it to a hot poker searing their insides. Between 2 and 7 percent of patients -- mostly young children and the elderly -- develop hemolytic uremic syndrome, which can lead to death. HUS sets in when Shiga toxins ravage the cells lining the intestines. The bleeding that ensues permits the toxins to stream into the circulatory system, setting up a cascade of damage similar to that of rattlesnake venom. The toxins tear apart red blood cells and platelets, leaving the victim vulnerable to brain hemorrhaging and uncontrolled bleeding. Clots form in the bloodstream, blocking the tiny blood vessels around the kidneys, the middle layer of the heart, and the brain. As the kidneys give out, the body swells with excess waste fluids. Complications ripple through all major organ systems, leading to strokes, blindness, epilepsy, paralysis, and heart failure. Though doctors can manage HUS symptoms, and are working on new ways to stymie the toxin, they currently can offer no cure or even effective treatment.

For public health officials, the emergence of E. coli O157:H7 is an object lesson in how a new pathogen can lie low in the environment, biding its time until humankind changes a certain activity and in so doing rolls out a red carpet. Like other emerging pathogens, such as the AIDS virus, 0157 had struck long before it caught the attention of public health officials. In 1955, a Swiss pediatrician in a dairy farm area first described HUS, which physicians today consider to be a gauge of E. coli O157:H7 infection. Over the ensuing years, the number of cases kept rising, suggesting that O157 was quietly spreading. In 1975, doctors took a stool sample from a middle-aged California woman with bloody diarrhea, cultured the apparently rare bacterium and sent it to the CDC, where it sat in storage until the McDonald's outbreak prompted researchers to scour their records for earlier evidence of the vicious organism. In other words, for nearly 30 years before the first bona fide epidemic, E. coli O157:H7 had turned up in scattered, sporadic cases of bloody diarrhea. It was out in the meat supply, but not in high enough concentrations to catch health officials' notice.

Where did E. coli O157:H7 come from in the first place? Scientists have pieced together a long, rather provocative history. Genetic lineages suggest that about 50,000 years ago, O157 and another closely related serotype -- O55:H7, which causes infant diarrhea in developing nations -- split off from the same mother cell. Since then, O157 has taken part in a series of biological mergers and acquisitions that left it as vigorous as one of today's giant pharmaceutical houses. Indeed, a 2001 study showed that O157, composed of more than 5,400 genes, picks up foreign DNA at a much faster rate than do other organisms. At some point, it acquired two deadly Shiga toxin genes after being infected by a bacteriophage, a tiny virus that insinuates its DNA into the chromosome of a bacterium. In the microbial world, phages are like squatters in Amsterdam, casually taking up residence in new bacteria, perhaps as a response to environmental stresses such as ultraviolet light or toxic chemicals. Bacteriophages are also the villains behind some of the most deadly human plagues; the genes coding for the cholera toxin, for instance, were borne on a phage. So what surrounding pressures compelled the phage carrying the Shiga toxin genes to light out for a new home in E. coli? In experiments on mice, Tufts University researcher David Acheson may have found the answer. When Acheson gave the animals low levels of antibiotics, the phage virus wildly replicated itself, and its magnified forces were more likely to infect other bacteria. Antibiotics also spurred the phage to pour out clouds of Shiga toxin. Acheson speculates that when farmers began the practice of feeding cattle small doses of antibiotics to spur growth, beginning in the 1950s -- perhaps not coincidentally, when the first reports of sporadic HUS in children came out -- they may have unleashed O157. More backing for this theory comes from epidemiological evidence. E. coli O157:H7 is a disease of affluent, developed nations -- which also happen to be the ones that feed growth-promoting antibiotics to livestock.

What worries Acheson and other scientists is that the restless phages that manufacture Shiga toxin may jump to other disease-causing bacteria. Actually, they've already proven they're disposed to do this, having set up home in about 200 other strains of E. coli. One of these, E. coli O111:H8, in 1999 caused a massive epidemic of nausea, vomiting, bloody diarrhea, and severe stomach cramps at a high school drill team camp in Texas, sickening dozens of the 750 teenage girls who attended. Though investigators never did find where the organism was hiding, they suspect it was either in the ice the girls used to soothe their parched throats during the drills or somewhere in the salad bar. Shiga toxin phages have also landed in Enterobacter and Citrobacter -- other bacteria that stir up intestinal disease. To find out just how prevalent these mysterious strains of dangerous E. coli may be, Acheson analyzed ground beef samples from 12 supermarkets in Boston and Cincinnati. The results came as a shock. He found Shiga toxin in a quarter of the samples -- toxin produced not by O157:H7, but by other kinds of E. coli. And this may not be the end of their roving, Acheson warns. "Suppose something like Salmonella developed the ability to produce Shiga toxins. That could be an extremely deadly pathogen." Not only is Salmonella common, but, more than E. coli O157, it has a talent for quickly invading the bloodstream, meaning it could speedily convey Shiga toxins throughout the body like tiny poison-tipped missiles. Even more problematic, the antibiotics normally used to treat E. coli O157:H7 infections may actually aggravate the illness, by kicking phages into overdrive and stepping up their production of toxins, leading to hemolytic uremic syndrome.

Along its evolutionary path, E. coli also became acid resistant, so impervious to a low pH environment that it can survive the incredibly sour bath in the human stomach. Grain-feeding cattle, which supplanted traditional hay feeding after World War II, may have made the bacteria more acid resilient. Because of this acid tolerance, as few as 10 organisms are enough to cause infection. Having acquired a mean set of toxin genes, acid resistance, and other virulence properties, all E. coli O157:H7 needed to become a truly fearsome threat was access. That it acquired by spreading in domesticated cattle and then entering the gears of modern industrial meat production, all within the past 25 years. Unfortunately, O157 may have left the door open behind it. Other strains of E. coli, "if tweaked in the right way" by phages and the mobile rings of DNA known as plasmids, could negotiate the same path, says Tom Whittam, a biologist at Pennsylvania State University who has studied O157 evolution.

Research is under way on vaccines that would prevent cattle from carrying O157, and on feed additives -- including competing intestinal bacteria -- that would eliminate the pathogenic organism in livestock. Thoroughly cooking ground beef to a temperature of 160 degrees Fahrenheit is the proven method of killing E. coli O157:H7. But in the United States, the organism retains a fighting chance because of the American love affair with rare burgers, which practically guarantees that one man's meat will be another man's poison. As a restaurant menu in suburban Dallas proudly informs its customers: "The Department of Health suggests MEDIUM-WELL for any ground beef product. Our burgers are cooked MEDIUM (PINK) unless you request otherwise."

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