Evelina Guirado, PhD

Senior Research Training Fellowship: Enzymes that Make Sugar Coating in TB Bacteria May be Target for Drug Therapy

Tuberculosis (TB) is a disease that affects one-third of the world's population, resulting in the death of nearly 2 million people each year. With resistance to current TB drugs on the rise, there is an urgent need for new TB therapy. With an American Lung Association Senior Research Training Fellowship, Evelina Guirado, PhD, is starting research on a key component of the bacterium that causes TB—the cell wall—which may yield clues that could be used in the development of new treatments.

Dr. Guirado is studying what happens in the initial stages of TB infection. She is focusing on the relationship between the Mycobacterium tuberculosis (Mtb) cell wall and an immune cell called the macrophage, which usually engulfs and destroys bacteria and foreign particles in the lungs but not Mtb. The Mtb cell wall includes molecules called lipoglycans which are decorated with a sugar, mannose, resulting in a sugar coat over the surface of the bacteria. Previous research provides evidence that this sugar coating plays an important role in the immune system's recognition of TB and its response to it. In fact, sugar coating may help the TB bacteria to survive in the lung and cause infection.

Dr. Guirado hopes to identify key enzymes that make GDP-mannose, an essential building block for the mannose coating of lipoglycans. She will alter the levels of genes involved in the production of GDP-mannose, looking at what happens both when more enzyme is produced and when none is produced, to determine their impact on mannose production in the Mtb cell wall and on the interaction between the TB bacteria and macrophages. "We want to manipulate those genes to see how it affects the macrophage's response to Mtb," she says. "The cell wall of Mtb is an attractive drug target, since mannose has been shown to be essential for the survival of mycobacteria and a number of current antibiotics target molecules in the cell wall," Dr. Guirado says. "If we find out that having too much of these enzymes that build up the TB cell wall helps the bacteria survive, then scientists could design a drug to block these enzymes."