How do you weaponize a rabbit?

There are four major infectious agents that officials fear terrorists will turn into potent bioweapons. The first three you know — smallpox, anthrax, and the plague. The fourth? An itty bitty bacterium that wikes to wive in bunny wabbits.

Don't let its host of choice fool you — tularemia is a serious disease. Humans can contract the nastiness through the bites of ticks and flies or handling the corpses of infected bunnies. Failure to cook said bunnies thoroughly will also make you sick. And that's not all. Back in 2000, 15 residents of Martha's Vineyard came down with "rabbit fever" in a single season — an outbreak thought to have started when someone ran over an infected rabbit with a lawnmower.

Obviously, if an errant brush hog can transmit the disease, a terrorist with an aerosol device could wreak some serious havoc. This isn't merely the plot of a Tom Clancy novel. The United States, Russia, and Japan all experimented with tularemia's use as a bioweapon during World War II. That's why researchers at the Lawrence Livermore National Laboratory (LLNL) are peering into the bacterium's inner workings to learn how we might fight such an outbreak. And they're finding tularemia to be a rather sneaky microbe.

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In humans and rabbits, tularemia evades the immune system by hiding out in white blood cells — the very sentries we rely upon to hunt invaders. Common signs of the disease include ulcers at the site of insect bites, swollen lymph nodes, and flu-like symptoms such as fever, muscle aches, and fatigue. If left untreated, rabbit fever can kill, as it did with one of the cases in the Martha's Vineyard outbreak.

But as potentially dangerous as tularemia is, there's still a great deal we don't know about it. For instance, until Amy Rasley and her team at LLNL started studying the bacteria, we had no clue how it survived in the environment — i.e., outside of humans, bunnies, and ticks. But Rasley's research has shown that when tularemia is in a bind, it can seek refuge in an amoeba, which are surprisingly similar physiologically to our white blood cells. Once inside, the bacterium becomes encapsulated in dormant cysts where it can remain until better opportunities arise.

Oh, but that's not nearly all. One of Rasley's colleagues, Geoffrey Feld, has been using x-ray crystallography to unravel the secrets of tularemia's survival trick. (Feld discussed the LLNL team's findings last weekend at an annual meeting of the Biophysical Society.) It seems tularemia is capable of secreting special proteins that might actually trigger the amoeba's cyst-making response. In other words, the bacterium does its best Frank Underwood impression and tricks the amoeba into giving it an office.

"If we're able to better characterize these proteins," said Feld in an interview, "then maybe we can start thinking about new countermeasures against tularemia based on how they work."

More research will be needed, of course, but the findings are promising — and welcome, given how little we know about the bacteria. Though the Centers For Disease Control and Prevention reports an average of just 130 human cases of tularemia each year, the agency takes the potential for its use in bioterrorism very seriously.

As an epidemiologist with the CDC's Division of Vector-Borne Diseases, Kiersten Kugeler says tularemia is a cause for concern because it's both highly infectious and widely available in nature. "CDC operates a national program for bioterrorism preparedness and response which includes stockpiling antibiotics to treat infected persons," she said. And just last week the CDC announced a cooperative effort with other federal agencies, international organizations, and foreign governments to launch the Global Health Security Agenda, which Kugeler said is designed to "standardize and unify response to disease outbreaks and close gaps in surveillance and response."

In other words, the CDC's got your back when it comes to a doomsday scenario involving tularemia. Furthermore, Kugeler says terrorists would require technology of "substantial sophistication" to weaponize rabbit fever on a large scale.

Then again, sometimes the simplest methods work best. There's some evidence to suggest that the Hittites used rabbit fever against their enemies over 3,300 years ago — making it the first known instance of bioterrorism. The Hittites' method? Leaving infected rams along the roads traveled by their enemies. After all, who can resist a free ram?