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Countering Bioterror:
The New Threat of Plague

by Alicia P. Gregory

Susan Straley isn't a bioweapons expert. But she's well aware of the noxious potential of Yersinia pestis, the bacterium she's studied since 1979.

"Inhaling as few as 100 of these bacteria can cause pneumonic plague," says Straley, a professor of microbiology and immunology who came to UK in 1983. Given the fact that scientists estimate each square centimeter of our skin teams with an average of 100,000 bacteria, these 100 bugs pack an extraordinary punch.

"As little as one day after inhalation you start showing severe symptoms of pneumonia, and the next day you could be dead," she says, adding that's a very narrow window for correct diagnosis and treatment.

What's even more frightening is that although researchers have been studying Yersinia pestis for more than 100 years, very little is known about pneumonic plague. Most of what they've learned focuses on bubonic plague, the much more common form of the disease spread by infected fleas. Bubonic plague killed 25 million people in Medieval Europe and continues to kill up to 2,000 people worldwide each year.

Photo of Susan Straley and Tanya MyersBubonic plague expert Susan Straley has 11 people on her research team, including Tanya Myers, a research analyst who has worked with Straley for three years.

The bioterrorism potential of an aerosol release, and the inevitable social turmoil that would result from a pneumonic plague outbreak, landed plague on the CDC's bioagent hit list. This is why Straley has begun to apply everything she knows about the spread of bubonic plague to the rarer pneumonic form.

She describes the route of infection for bubonic plague: "Pretty early after the bugs are injected into a mammal, they will come into contact with host cells. And they are thought to enter some of those cells, particularly our innate defense cells called macrophages." Before the immune system has a chance to gear up, macrophages serve as a safe haven for Yersinia pestis to start manufacturing a special delivery system for their toxins.

Meanwhile, PMNs (polymorphonuclear neutrophils), the body's own "bug terminators," are activated by the immune system. PMNs do battle with the bugs, but the bugs have the upper hand because, Straley explains, as they multiply they turn on properties that prevent them from being destroyed by the PMNs.

"Now the bugs get into lymph, the fluid in your tissues circulated by the lymph system. It's like a series of open culverts. The bacteria enter the lymph tubes and are collected and filtered by lymph nodes. There are lots of PMNs and macrophages waiting in the nodes, and the battle continues." The chemical signals from this battle set off a huge inflammatory response: more cells come in to join the fight. The result—a swollen lymph node called a bubo. "The time from infection to bubo is about five to seven days," she says.

The lymph carries the bacteria into the blood, and from there they attack the blood-filtration organs, the spleen and liver. More PMNs and macrophages in those organs fight the infection. "Some of the bugs are killed for sure," says Straley, "but the bacterial numbers just overwhelm the immune system and bugs go everywhere.

"They wind up in the lungs, and in the terminal stages of bubonic plague you can develop pneumonic plague." In this contagious and highly dangerous stage, coughing can spread the disease from person to person.

In the case of direct pneumonic plague infection (which occurs in less than 14 percent of naturally occurring plague cases), the inhaled bugs have already adapted to the body of the first person, so they arrive fully armed with their toxin-delivery mechanism. Straley says this gives the bacteria a head start in the race against the body's defenses. As in bubonic plague, the bacteria first encounter macrophages—in this case alveolar macrophages, the lung's defense cells. "Some of the bacteria go into macrophages, you get an influx of PMNs and then inflammation. Part of inflammation is fluid influx, so your lungs fill up and you can't breathe," says Straley. "The bacteria also spread to the lymph nodes and the blood, so the basic process is the same as in bubonic plague, but we really know very little about the specifics."

One of the major areas of Straley's research grew out of the overarching question: "Why are these bugs so virulent?" She says their incredible capacity for causing disease has to do with a specialized delivery mechanism for toxins that looks remarkably like a pushpin you'd stick into a bulletin board.

"This pushpin is a molecular machine," she says. "The machine has maybe 21 parts—some of them moving parts. The bugs assemble these to get their toxins into cells."

This pushpin machine's official name is the Type III Secretion System. "UK participated in its discovery," Straley says. "A number of other human pathogens have this system—Salmonella, Shigella, Chlamydia, E. coli 0157:H7. Right now many scientists and drug companies are actively working on ways to target this system."

"When the needle—the part that sticks out—comes in contact with a host cell, it punctures the cell and samples the cytoplasm [the cell's internal fluid]. In response to the low calcium environment inside the cell, the bug's secretion mechanism is activated, and it sends toxins right into the host cytoplasm."

These toxins are called Yops, which stands for Yersinia outer proteins. "These Yops mimic key cell biological reactions and modify them in a way that is advantageous to the bacteria," Straley says. Six Yops have been identified, and she says there are probably more. "One of the bug's early high-priority activities is to prevent being engulfed and destroyed by macrophages and PMNs; three of these Yops participate in that."

Of the six Yops that have been identified, one is still an enigma—YopM. "This Yop gets delivered to the cytoplasm just like all the others, but for some reason it hitches a ride with the cellular trafficking system and winds up entering the cell nucleus. If we can identify what YopM does inside the nucleus, it may shed light on why these bugs are so virulent."

Photo of YopM under the microscope This image shows the distribution of the protein YopM in cells four hours after infection. The whitest areas show the highest concentration of YopM. The strands that stick out are Yersinia pestis, the bacteria that cause plague.

Another piece in this deadly puzzle is V antigen—"V" stands for virulence. "The antibody against V antigen can protect you from plague, so it's a candidate for inclusion in an improved plague vaccine which is on the fast-track," Straley says. (There is no longer a licensed plague vaccine in the United States.) "Unfortunately, we don't know fully how V works. It does multiple things, which is the problem."

Straley explains that V antigen, in some way, regulates the gate mechanism that activates the pushpin machinery. It also sponsors the delivery of Yops. "If you don't have V, you don't have Yops delivery." And V antigen, Houdini-like, gets outside the bacteria all by itself—sometimes it goes out with the Yops through the pushpin, sometimes it doesn't.

"We know V antigen down-regulates the immune system," she says. When the immune system activates, it's incredibly potent. It has built-in regulators that stop it when the infectious insult is over and return things to normal. "Well, V makes this happen early, which is one of the reasons these bugs multiply so rapidly."

Straley's primary UK partner in plague research is colleague Robert Perry, whose work on Yersinia pestis's iron-transport systems earned him a 2001-2002 University Research Professorship. Straley and Perry are collaborating on a project focusing on the development of pneumonic plague that's getting down to the nitty-gritty of how the bacteria adhere to the lungs.

"One of the first things that happens in any infection is the bugs attach to something. We want to identify what they are using to adhere, with the idea that if we could identify the molecules involved, we could make therapies to counteract those molecules. So some kind of vaccine or drug that would be effective early in pneumonic plague could prevent the infection from happening."

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