September 23, 2009

The Secret Life of Bacteria

New National Academy of Sciences member Ralph Isberg delves into the infinitely complicated ways that pathogens invade healthy cells

By Taylor McNeil

In July 1976, a mysterious pneumonia-like infection killed 34 people attending an American Legion convention in Philadelphia. The culprit was isolated the following year: a hitherto unknown bacteria, which was given the name Legionella pneumophila.

Ralph Isberg, who was elected this year to the prestigious National Academy of Sciences, has found that pathogenic bacteria enter and inhabit cells in many different ways. Photo: Alonso Nichols

Nearly 10,000 people are stricken annually with what is now known as Legionnaires’ disease, which can be lethal in at-risk populations, including the elderly and those with compromised immune systems.

But Legionnaires’ also infects relatively healthy people. Ralph Isberg, a professor of microbiology at the School of Medicine, tells of a friend in his mid-60s who died after he inhaled steam at a sauna that contained the L. pneumophila bacteria.

“It’s not as uncommon as you might think,” says Isberg, who is a faculty member with the Molecular Microbiology Program at the Sackler School of Graduate Biomedical Sciences. “It’s amazing how many people walk through the door, and they know a relative who had Legionnaires’ disease.”

Bacterial infections are so common—and so commonly fought with antibiotics—that you might think there was not much left to discover about them. But in fact the opposite is closer to the truth. Isberg, who has studied bacterial infections for more than 20 years, is investigating such seemingly basic questions as how pathogenic bacteria get inside healthy cells and how they manage to survive and grow—and why they aren’t immediately zapped by our immune systems.

For his work, Isberg was elected this spring to the prestigious National Academy of Sciences. Academy members—there are now about 2,150, including nearly 200 Nobel Prize winners—are elected in recognition of their distinguished and continuing achievements in original research.

The Little Red Light

As a postdoc in the mid-1980s at Harvard, where he had earned a Ph.D., Isberg wanted to test a particular path that he thought infectious bacteria might use to enter healthy cells. He proposed an experiment to convert the ordinary, unthreatening lab organism E. coli into a bug that penetrates healthy cells. It won’t work, he was told.

Undaunted, he went ahead with the experiment. He took DNA from the bacterial pathogen Yersinia pseudotuberculosis, a close but non-lethal cousin of the pathogen that causes bubonic plague, and inserted it into the non-pathogenic E. coli. The modified E. coli was able to trick a host cell into letting it in, with help from a protein that Isberg named “invasin.”

From that moment, Isberg had a mission: understanding how bacteria get into and then grow in host cells. He soon turned his attention to the bacteria that’s responsible for Legionnaires’ disease. “It is a fascinating organism, and it didn’t take long before a large portion of my lab was working on it,” Isberg says. This particular bug is easy to work with: researchers can grow a colony of billions of Legionella pneumophila in petri dishes in just a few days.

It’s possible to grow a colony of billions of bacteria in just a few days. Photo: Alonso Nichols

Isberg and his colleagues—15 graduate students and postdoctoral researchers work in his lab—have found that pathogenic bacteria have multiple modes of attacking cells and using them as hosts. If one way doesn’t work, no problem: go to Plan B. “It looks very much like how we design space travel,” Isberg says. “Take the space shuttle: one system breaks down, and another system makes up for it. The only reason you know the system is broken down is that there’s a little red light that says it’s broken down, because otherwise the spaceship is still functioning perfectly fine. It’s the same thing here.”

That is, even when bacteria are not operating normally, they seem to carry on as if nothing at all were amiss. “Our problem is we don’t know what the backup mechanism is and what the primary one is,” says Isberg, a Howard Hughes Medical Institute investigator.

For instance, in their quest to discover how infectious bacteria thrive within a host cell, Isberg and his colleagues have identified a number of significant genes. These genes help create channels through which L. pneumophila can move proteins into the host cell. The proteins can, in turn, help the bacteria grow. But even when the researchers introduce genetic mutations that throw a wrench into this process, “the bug still seems happy and it grows fine,” Isberg says.

“In other words, we can see the red light,” he laughs, “but that’s about it.”

Forward March

One way to combat the growth of pathogenic bacteria in host cells is to discover how they manage to grow and proliferate, and then attack that front. A colony of bacteria growing within host cells is like an army in enemy territory: it needs multiple supply lines to keep marching forward, Isberg says. “If you knocked out one supply line, you’d have another to get the food supplies through,” he notes. “It’s the same exact thing here.”

In a military campaign, supply lines come by land, sea or air. “It’s true in the host cell, too; they come through different sources,” Isberg says. “But the bug doesn’t care how nutrients come, as long as they get there.”

Bacteria also have to fend off the body’s immune system. The best strategy is to avoid detection. If the immune system hones in on the bacteria and attacks, the host cell simply dies, taking the bacteria with it.

But keeping a low profile doesn’t always succeed. In Legionnaires’ disease, for example, the infected cells cause fluid to build up in the lungs, which can be fatal. “The bug’s got to be able to grow without doing that,” Isberg says. After all, if the person with the disease doesn’t survive, the bug dies just as surely as it would if it were wiped out by the immune system.

That’s not a problem for the other organism Isberg studies, Yersinia pseudotuberculosis, a food-borne, gastrointestinal illness. The bug grows in the intestine, but takes its time affecting the people it inhabits. “The less severe the disease is, the more it can sit around in the host and spread to other hosts,” he says.

The deep understanding of bacterial mechanics that Isberg and his colleagues are building could someday help eradicate bacterial diseases. The best outcome would be drugs “that will kill an organism and prevent it from growing, under any circumstance, in any environment,” Isberg says.

Taylor McNeil can be reached at

Article Tools

emailE-mail printPrint