Grant: Project Grant - Priority Announcement: Infection and Immunity

It is well established that fungi protect themselves from nitric oxide (NO), an antimicrobial compound produced and released by macrophages and other immune cells in host defense. Although fungal species have evolved few strategies to detoxify the adverse effects of NO, a prominent mechanism consists of producing the heme-dependent flavohemoglobin Yhb1, which neutralizes NO toxicity by converting NO into innocuous nitrate. Despite its essential protective role, the mechanism whereby Yhb1 is regulated and acquires heme for its NO detoxification activity remains poorly understood. Our research model is based on the unique biology of the fission yeast Schizosaccharomyces pombe. This microorganism is one of the best-understood model system to investigate the mechanisms by which eukaryotic cells acquire exogenous heme. This tractable model allows the use of the power of genetics to selectively block heme biosynthesis, setting conditions to investigate the mechanisms by which external heme is taken up by the cells, and eventually distributed to hemeproteins such as Yhb1. The goal of this research is to provide a better understanding of key mechanistic aspects on how Yhb1 becomes active in a heme-dependent manner to confer resistance to NO. This information will help us achieve our long-term goal of identifying new ways to circumvent NO resistance mediated by Yhb1, thus improving the treatment of infections by fungal pathogens.