A mystery recently solved by a team of Rocky Mountain Laboratory researchers on the deadly bacterium that causes tularemia may someday save lives of people inflicted with other serious diseases, including cancer.
Solving the mystery required a new piece of equipment at the Hamilton laboratory and the persistence of a young scientist with roots that run deep in the Bitterroot Valley.
Tularemia is a life-threatening disease caused by the bacterium Francisella tularensis that can be spread to humans through contact with an infected animal or from bites of a mosquito, tick or deer flies. In some places in the country, people have been infected after running over a rabbit with a lawn mower and breathing in the bacteria.
As few as 10 bacteria is enough to cause the disease, which has a death rate up to 60 percent.
The disease is often hard to detect because of the stealth-like nature of the bacteria which inhibit the inflammation that would normally serve as the trigger for people to seek medical attention.
Researchers at RML knew the bacterium was able to evade and suppress the body’s natural immune response, but they didn’t know exactly how that occurred until Corvallis native Forrest Jessop and a piece of equipment called a Sea Horse arrived at the laboratory about two years ago.
Jessop traces his interest in science back to Corvallis High School where he participated in a project that sought to determine the diversity of the local mountain goat population through DNA gathered from their scat.
Though that project failed, it set Jessop on a new path that would eventually lead him back to the Bitterroot Valley as a RML scientist studying a disease that once threatened westward settlement.
“There are two reasons it’s infamous,” said Dr. Katy Bosio, RML’s bacteriology lab chief. “In the wild, it’s carried by ticks and mosquitoes, but it can infect just about anything that walks, crawls or swims on this Earth. One of those things are rabbits. They are extremely sensitive. If a rabbit is infected, it will probably die.”
In the early 1900s, rabbits were an important food source for settlers and antibiotics weren’t available.
“There were a lot of people contracting tularemia,” she said. “It was impacting the settlement of the West.”
Today, the disease is less prevalent. On average, about 200 people a year are infected in this country. The last couple of years have been a bit worse with numbers about double the average.
“It’s not a major health threat, but it’s a persistent one,” Bosio said. “You can find it everywhere in the U.S., including Montana.”
In Bosio’s lab, the bacterium is known for its ability to evade and suppress the body’s natural defense systems.
“This bacterium is really, really good at doing this,” she said. “It does it on multiple levels...It’s a very stealthy organism.”
Jessop was hired by Bosio at about the same time a new tool called a Sea Horse, which allowed researchers to study metabolic processes inside cells in real time, came to the lab.
When a cell is invaded by a bacteria or a virus, it kicks into a high gear to fight off that infection. That interaction is hard to study without a machine that can offer an instantaneous look.
Researchers knew that somehow the tularemia bacteria were able to keep cells from increasing their metabolic rate, but they didn’t completely understand how it managed to do that.
The metabolic change is normally driven by cells breaking down sugars to drive the shift in metabolic rates, but somehow the tularemia bacteria was able to keep the cell from changing its energy source.
“We don’t know of a single other bacterium that can do that when it enters a cell,” Bosio said. “It’s super stealthy. It can get in and begin to replicate without activating that change. It’s actively telling the cell that everything’s cool, just go about your business. Don’t pay any attention to me.”
Like many other bacteria, it’s encapsulated by a sugary coating that acts like an invisibility cloak inside the cell. Unlike other bacteria, that capsule has the ability to manipulate the immune response by telling the cell’s powerhouse — the mitochondria — that everything is OK.
That allows the bacteria to slowly replicate in the cell while preserving the health of the cell and preventing an inflammatory response.
For the first two-thirds of the 16 to 18-hour infection, the cell doesn’t realize that something very bad is about to happen.
Jessop was the first to see what came next.
As he watched through a microscope and a series of time-lapse photos, Jessop saw the mitochondria’s function tank. As the cell’s energy level dropped, it went through a process called oncosis. Without the energy needed to keep the pumps operating that keep water and minerals at optimum levels, the cell filled up a like a balloon.
That proved to be the signal for the bacteria to begin to hyper-replicate.
“It may go from having 50 bacterium in a cell to having thousands in a matter of a few hours,” Bosio said. “It all happens very quickly. Eventually the cell explodes and that releases all that bacteria.”
Since it happens so quickly, there’s still very little inflammation.
“Eventually with tularemia, there is an inflammatory response, but by that time it’s spread to other parts of the body,” she said. “When something becomes that sick, it will often be still and can be easily captured and eaten. Whatever eats the animals gets the infection.”
This new understanding of how the bacteria operate could lead to research that could create vaccines or new treatments for tularemia. Beyond that, scientists may be able to tap into molecules within the bacteria to slow inflammation caused by other pathogens.
“This is study that has a dual benefit,” Bosio said. “We not only were able to understand some interesting bacteriology, we may also discover new ways of targeting that bacteria more efficiently in ways that don’t rely on traditional antibiotics. And we could eventually repurpose some of those molecules to develop more effective, novel treatments to other disease manifestations.”
Jessop said it was “really cool” to know that he was the first scientist to see the exploding cell infected with tularemia.
“Being the first to see something is exciting, but what becomes more exciting to you as a scientist is now that we know this, we can do that and that,” Jessop said. “If this is true, then we might be able to go there.
"In some way, it is opening those new doors is what’s really exciting. That potential of going through another door and finding what’s next is why you’re a scientist.”