Disruption of a key enzyme in the fungus Cryptococcus neoformans a common cause of infection of the central nervous system in patients such as organ transplant recipients who lack a functioning immune system -- led to a significant loss of fungal virulence in mice, the team found. That loss of virulence stemmed from the fungus's inability to launch a counterattack against components of the innate immune system, the body's first line of defense against infection, the study showed.
The Duke-based team -- led by HHMI geneticist Joseph Heitman, M.D., director of Duke's Center for Microbial Pathogenesis, and HHMI biochemist Jonathan Stamler, M.D. -- reported their findings in the Nov. 11, 2003, issue of Current Biology. The work was funded by the National Institutes of Allergy and Infectious Diseases and the Burroughs Wellcome Fund.
The "fungal defense" enzyme, called flavohemoglobin, is prevalent among many bacterial and fungal pathogens, Heitman said, which suggests that the findings in Cryptococcus are likely relevant to other infectious microbes. New drugs that target these enzymes might therefore represent effective treatments for a wide range of infectious diseases, he said.
The human immune system uses a two-pronged mechanism to fight infection: a rapid innate response and a slower adaptive response that depends on the production of antibodies. Key components of the innate immune system are "search-and-destroy" cells called macrophages that engulf and kill invading pathogens. Macrophages kill infectious microbes using a combination of oxidants, including hydrogen peroxide, nitric oxide and related molecules.