Project Summary / Abstract Fungal pathogens take a devastating toll on human health worldwide, and fungal infections are on the rise due to the growing population of immunocompromised individuals. Treating fungal infections is extremely difficult, as fungi are closely related to humans and there are very few drugs that kill the fungus without host toxicity. With the emergence of drug resistance, the development of new therapeutics is now crucial. To address this unmet medical need and identify new targets for drug development, it is critical to uncover mechanisms that enable these pathogens to cause human disease. I have developed a powerful approach to study the front line of human defense against these fungal pathogens. Host innate immune cells recognize and engulf the invading pathogens, but the fungal cells are able to adapt and trigger immune cell death. I recently discovered that this immune cell death requires fungal cell wall remodeling and the NLRP3 inflammasome. However, the specific trigger and mechanisms involved remain enigmatic. Here, I propose an interdisciplinary approach to examine mechanisms by which fungi are able to induce host cell death, and the host pathways that are required for responding to the invading pathogen. Our global analyses of fungal gene expression, gene function and host immune responses will provide a high-resolution portrait of this host-pathogen interface, and reveal new targets for therapeutics to save human lives.