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Looking for clues about disease affecting cattle and people

Clay Caswell (left), assistant professor of bacteriology, seeks to better understand brucellosis with Ph.D. students James Budnick and Lauren Sheehan.

Clay Caswell (left), assistant professor of bacteriology, seeks to better understand brucellosis with Ph.D. students James Budnick and Lauren Sheehan.

A Virginia Tech researcher is hoping to better understand a bacterium responsible for both spontaneous abortions in cattle and an inconsistent and sometimes fatal fever in humans.

Clay Caswell, assistant professor of bacteriology at the Virginia-Maryland College of Veterinary Medicine and an affiliate of the Fralin Life Science Institute, has focused his attention on Brucella. While his colleagues at the veterinary college have spent years developing more-effective vaccines, Caswell is taking a different approach to better understand the molecular basis for Brucella infection.

Brucella lives inside a host immune cell called a ‘macrophage,’ “ said Caswell, who is studying how two small regulatory RNAs allow the bacterium to survive there. “The paradox is that it’s living inside the very cell that’s trying to destroy it.”

Caswell has received funding from the Virginia Agricultural Experiment Station to characterize a novel genetic pathway linked to the bacterium’s virulence. He has also been awarded recent grants from the American Heart Association and the National Institutes of Health to develop the basic science needed to develop treatments in humans who are exposed through unpasteurized milk and other means.

“Brucellosis is the most common zoonosis in the world,” Caswell said. There is no human vaccine for the disease, which infects approximately 500,000 people worldwide every year.

“It is very hard to treat, often requiring two rounds of antibiotics, with a relapse rate of up to 15 percent and the potential for chronic infections. It has a low mortality rate, but when it is fatal, it is often due to a heart infection,” Caswell said.

Other researchers at the veterinary college are developing more-effective brucellosis vaccines for cattle. The U.S. Department of Agriculture granted a provisional license for a vaccine developed by Gerhardt Schurig, professor of immunology and former dean, in 1996 and a full license in 2001. Today, the cattle vaccine developed at the veterinary college is used by farmers and veterinarians worldwide.

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Virginia Tech researcher discovers possible drug target for sleeping sickness

Zachary Mackey

Zachary Mackey in Biochemistry is doing research on how to cure sleeping sickness, which is carried by the tsetse fly.

Zachary Mackey is trying to deliver a stern wake-up call to the parasite that causes sleeping sickness, a neurological disease that threatens millions of lives in 36 countries in Africa, according to the World Health Organization.

Mackey identified a protein vital to the sleeping sickness parasite’s good health. Disrupting the protein with drugs could potentially make it impossible for the parasite to reproduce and survive, and thereby reducing its danger to human health.

The discovery suggests multiple ways to disrupt the protein’s function, said Mackey, an assistant professor of biochemistry in the College of Agriculture and Life Sciences, an affiliated faculty member in the Fralin Life Science Institute, and an affiliated researcher in Virginia Tech’s Vector-Borne Disease Research Group.

Sleeping sickness is caused when the vector-borne parasite Trypanosoma brucei crosses the blood-brain barrier during the late stage of infection.

The native African tsetse fly transmits the parasite through a painful bite, allowing it to spread through the body, causing fever, headache, and intense aches and pains.

When the parasite spreads to the brain, it causes swelling, slurred speech, confusion, and difficulty walking, followed by coma and eventually death.

Mackey thinks that overexpressing, depleting, or blocking the protein — known as proliferating cell nuclear antigen — represents three ways this protein could be targeted in the parasite, broadening the types of small molecules or drugs that can be developed to treat the disease.

Though a few drugs currently exist, they are either very expensive or have extremely powerful side effects due to their toxicity, according to Mackey, who is also an affiliated researcher in the Virginia Tech Center for Drug Discovery.

Mackey now investigates how altering the amount of protein kills the parasite. Once he better understands how this protein regulates the parasite’s life cycle, he can partner with chemists to synthesize small molecules that target the protein’s disruption.

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