Assignment

The plague never went away after widespread outbreaks during medieval times. It's still with us, but its threat is much different. Now, experts fear it could be used as a weapon of mass destruction.

Wikimedia Commons

Black Death Threat

UNC's Bill Goldman battles the next outbreak of the plague before it happens by Mark Derewicz.

In 2008, on the Grand Canyon's southern rim, a biologist named Eric York found a dead mountain lion with a bloody nose but no other signs of trauma. He took it back to his garage to perform an autopsy, which revealed nothing unusual.

Two days later, York developed a bad cough. He felt weak, achy, tired. His doctor told him he had a flu-like illness and sent him home. Two days after that, York was dead.

This time, the autopsy did reveal something. York was stricken with the plague, also known as the Black Death, the same disease that wiped out half of Europe during the fourteenth century. Public-health officials gave antibiotics to everyone who had come in contact with York.

No one else died. Disaster averted. But how did York's doctor miss something as uniquely horrifying as the plague?

Turns out just about every doctor would've missed it, according to UNC's Bill Goldman. "The first symptoms of the plague really are indistinguishable from the flu," he says. But unlike the flu, the plague is already well on its way to shutting down the lungs by the time a patient begins to feel sick. It's a sneaky, extremely contagious, and fatal disease, three reasons why governments and researchers think the plague is a bioterrorism threat-a twenty-first-century weapon of mass destruction.

In medieval times of war, combatants would catapult infected bodies over city walls. Today, a bioterrorist attack would be stealthier and a lot more dangerous.

After the anthrax scare of 2001, the U.S. government pushed for scientists to research various biological warfare threats, such as Yersinia pestis, the bacterium that causes the plague. "I hate to put it this way, but terrorists aren't going to unload a bunch of rats or fleas into town," Goldman says. They'll culture the bacteria in massive amounts. "They'll try to spread the disease by an aerosol," he says.

Victims wouldn't smell it or see it. They wouldn't even feel a thing at first, but the disease would be on a rampage. Thousands of people would get sick but have no idea they had the plague until it was too late to save them.

The plague is such a silent killer because Yersinia pestis doesn't trigger the same sort of quick immune response that most bacterial infections do. When a person contracts the plague, the bacteria multiply from a few microbes to a billion within 48 hours. But for some reason the lungs-typically very good at getting rid of undesirables-don't respond.

In the case of Eric York, doctors had no way of distinguishing his illness from the flu. Only when symptoms worsen-vomiting, difficulty breathing, coughing up blood-does the plague give itself away. "By then, when it's recognizable as pneumonic plague, it's too late to treat it," Goldman says. The lungs are overrun with bacteria. The pulmonary system is all but shut down. The circulatory system can't deliver antibiotics into the lungs. Patients suffocate to death. They just can't breathe anymore.

"Here's the question we wanted to answer," Goldman says. "Is Y. pestis avoiding detection, or is it actually suppressing the immune responses of the lung?" The answer would give his team clues about how to make the plague less like the Black Death and more like the flu, at least in terms of patient prognosis.

Goldman's samples of Yersinia pestis came from a repository that got its specimens when a Colorado woman died of the plague in 2000. She had been infected by her cat, which had probably gotten hold of an infected rodent. These specimens are just as deadly now, which is why Goldman's team was put through stringent security checks before being allowed to work with the organisms. The FBI has active files on each lab member, including Goldman.

When no one is working in the Goldman lab, sealed and locked doors separate humans from the containers that hold the bacteria. Lab technicians change into protective clothing in a designated chamber between the outer lab and the inner lab where they handle the samples. They attach to their heads a device that continuously pushes air downward to lessen the chance that they'll breathe in a pathogen. They open specimen containers only under a special hood, into which they reach with gloved hands to conduct experiments.

One of the reasons Yersinia pestis is such an aggressive killer is because it contains a particularly nasty plasmid-a segment of DNA that is not part of a bacterium's chromosomes but can replicate and transfer into other living things. Yersinia pestis picked up its deadly plasmid from some other organism thousands of years ago, Goldman says. He wondered how virulent the bacterium would be without that plasmid, so his team took it out and placed a droplet of the specimen on the nose of a single mouse. When the mouse breathed it in, the bacteria didn't multiply. In fact, they declined in numbers over four days.

The mouse never got sick. This proved that the plasmid is absolutely critical for lung infection to spiral out of control.

Then Goldman's team mixed the nonlethal strain of Yersinia with the deadly strain and documented how they behaved in mouse lungs. The deadly strain multiplied like mad, as Goldman expected, but so did the nonlethal strain.

In another experiment, his team documented how other, relatively harmless bacteria responded when the deadly Yersinia strain was present in the lungs. "Even the harmless bacteria are able to grow really well when Y. pestis is present," Goldman says. "They increase from a thousand to between one million and ten million organisms in the lung." Those once-harmless bacteria wind up aiding Yersinia in blocking the lung's air passages.

Although Goldman and his team have indicted that lone plasmid, they're still trying to pin down the mechanism that allows Yersinia to change the lung into such a permissive playground for pathogens. And if they find that mechanism? "What I'd like to say is, ‘Oh, that will lead us to a drug,'" Goldman says. "But it depends on what the mechanism is."

His team has already identified a Yersinia protein that helps the bacterium multiply inside the lung. "We have a patent on the idea of creating an inhibitor of that protein," Goldman says, "but we haven't found an inhibitor yet."

Disabling that lone gene might be less a cure than a shield to keep the disease from progressing so fast, which might give doctors more time to treat patients.

"You have to figure out how to defeat the main barriers to treatment," Goldman says. And in the case of the plague, the main barrier is the speed at which the disease takes hold. A person usually dies within three and a half or four days of contracting pneumonic plague. Goldman says that inactivating the protein his team has identified could keep patients alive longer than usual, and that would give antibiotics more time to work. "If you can change the speed of the infection," he says, "you've solved a major problem.

This approach wouldn't help everyone infected with the plague. It likely wouldn't have helped Eric York. But lengthening the time between initial infection and death could be enough to save thousands of lives after a bioterrorism attack.

"Imagine the worst-case scenarios," Goldman says. "An aerosol released that exposes a lot of people at once, and no one would have any idea they've been exposed. All of a sudden, everyone is sick. Early symptoms are indistinguishable from the flu."

In such cases, a cure would be best. A vaccine would be a close second. The next best thing would be to slow down the disease so treatment has a chance to work. "The plague is susceptible to antibiotics," Goldman says. "Just not in that last 24 hours."

Bill Goldman is chair of the department of microbiology and immunology in the School of Medicine. He received funding from a National Institutes of Health grant to the Southeast Regional Center of Excellence for Emerging Infections and Biodefense, which is headquartered at UNC-Chapel Hill.

Discussion Questions:

The Black Death and Bioterrorism

1. What caused Mr. York to get sick? Is there any obvious cautionary moral to this scenario?

2. Why did Mr. Your's doctor mistake the plague for the flu?

3. Why would the plague bacteria, Yersinia pestis, be an attractive pathogen for terrorists to use for bioterrorism?

4. Many pathogens trigger our immune system to start making antibodies soon after entry into the body. Within 10 days the immune response is usually able to overcome the disease and the patient recovers. It seems surprising that this pathogen, Yersinia pestis, seems to escape the normal immune response. Dr. Goldman wondered about this. "Here's the question we wanted to answer," Goldman says. "Is Y. pestis avoiding detection, or is it actually suppressing the immune responses of the lung?"

He discovered that the bacteria has a small extra chromosome, known as a plasmid.

He was able to prove that it was the extra plasmid that makes the bacteria more vicious.

When he took out the plasmid, the remaining bacteria was relatively harmless. He showed that other bacteria in the lungs were more harmful when the plasmid was present.

He proposed that the plasmid gene encoded a protein that somehow helped disable the immune system. He reasoned that if he could find a way to disable the protein made by the plasmid, that he could use that as a treatment to slow down the pathology of the disease until the patient's immune system caught up.

How could this treatment slow an epidemic caused by an act of bioterrorism?