The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, has awarded a two-year, $408,000 grant to Clay Caswell, assistant professor of bacteriology in the Virginia-Maryland College of Veterinary Medicine at Virginia Tech, to study the disease-causing mechanisms of Brucella abortus, the bacteria that causes brucellosis.
Worldwide, brucellosis is one of the most common zoonotic diseases? — those typically infecting animals that spread to humans. B. abortus can be naturally transmitted from animals, most commonly through direct contact or consumption of unpasteurized dairy products. Domesticated animals (cattle, goats, and swine) and wild animals (elk, bison, and feral swine) can carry the bacteria.
Brucellosis in animals causes sterility and abortion. In humans, it causes a waxing and waning — and sometimes debilitating — fever. Human brucellosis is difficult to treat and can relapse after antibiotic therapy. No human brucellosis vaccine exists.
“Given the intimate relationship between animals and humans and the zoonotic potential of brucellosis, tackling this type of disease requires a One Health approach,” said Caswell, whose laboratory is located in the Center for One Health Research, an interdisciplinary collaboration between the veterinary college and the Edward Via College of Osteopathic Medicine.
Brucellae live in large immune cells called macrophages. Their ability to survive and replicate within a cell meant to destroy them is key to their pathogenesis. Caswell’s research project will focus on how a transport system and the amino acid gamma-aminobutyric acid (GABA) make B. abortus pathogenic.
Understanding how molecular pathways control Brucella’s pathogenesis has important clinical implications, such as human vaccine development. An even more exciting potential, Caswell noted, is the development of novel therapies. “If we can target some of these pathways with novel treatments, we can interrupt the transmission of the disease.
“If novel therapies can provide a quick and effective treatment, there would be less need for a vaccine,” Caswell said.
The transport pathway to be studied has been analyzed in other bacteria, but not Brucella. Preliminary data, collected in large part by Jimmy Budnick, a doctoral candidate in Caswell’s laboratory, demonstrated that mutating the pathway significantly reduced B. abortus infection rates in mice. Even with these promising results, Budnick believes the most important question regarding this pathway is, “What is this system transporting?”
Caswell and his research team hypothesize that the transport pathway transports GABA, a well-known brain chemical that blocks messages between neurons. Their initial data confirmed this hypothesis and “pushed this project into fruition,” Budnick said. Previous research has described GABA’s influence on microbes’ responses to stressful acidic environments, Budnick noted. However, he explained, “This GABA-related stress response is not utilized in B. abortus, so we hypothesize an alternative function in Brucella biology.”
One alternative function might be the expression of genes, the units of heredity. “Studies have shown that GABA uptake by bacteria can cause the bacteria to upregulate the expression of certain genes,” Caswell said. Whether GABA influences gene expression in B. abortus and whether the transport pathway transports molecules other than GABA, are research questions that Caswell and his team will investigate.
Reiterating the One Health implications of the work, Budnick said that this research “could change our understanding of the role for GABA in microbes that affect human health. It is possible that other bacteria utilize GABA similarly to Brucella, thus changing how we understand host-microbe interactions in human and animal health.”
An Internal Research Competition (IRC) grant through the veterinary college’s Office of Research and Graduate Studies provided the financial support to collect the preliminary data. Caswell explained that this IRC grant “allowed us to springboard into the larger [R21] grant,” which funds exploratory and developmental research.
In addition to Budnick, a second graduate student will be recruited to contribute to this project.
Caswell’s infectious disease research contributes to Virginia Tech’s Global Systems Science Destination Area, which fosters transdisciplinary study of the dynamic interplay between natural and social systems. Researchers in this area collaborate to discover creative solutions to critical social problems emergent from human activity and environmental change.
— Alison Edward
