Most are contained by the body's immune system, but each year a few thousand people will develop chronic or life-threatening histoplasmosis disease requiring hospitalization and antifungal treatment. The antifungals currently used to treat the infection have undesirable toxic side effects requiring monitoring by a physician and may need to be taken for weeks or months.
is particularly good at avoiding detection by the body's immune system and surviving the immune response," said Jessica Edwards, PhD, a postdoctoral researcher at Ohio State University.
Respiratory histoplasmosis manifests with flu-like symptoms, often making diagnosis difficult. Rappleye says people with histoplasmosis have been mistakenly diagnosed with colds, the flu, and even lung cancer. "It depends on how familiar a physician is with histoplasmosis," he said.
Intrigued by the challenges of finding a new drug that would target the fungus without harming the human host, in 2012, Rappleye received pilot funding from Ohio State's Center for Clinical and Translational Science (CCTS) and the Public Health Preparedness for Infectious Diseases Program (PHPID).
Rappleye's team searched a library of commercially-available small molecules used by other investigators to find new antivirals or anticancer drugs. They performed a high-throughput phenotypic screen of 3,600 compounds looking for agents that inhibited fungal, but not human, cells.
To speed the selection process, Rappleye and Edwards engineered Histoplasma
cells with a fluorescent protein that made the cells glow red while inside of a living macrophage - the type of mammalian immune cell that Histoplasma
attacks and in which it reproduces.