Characterization of Anti-Fungal Inflammasome Responses and the Role of Caspase-8 in Innate Immune Signaling: A Dissertation

Abstract

Candida albicans is an opportunistic human fungal pathogen that primarily affects patients with immunocompromising conditions such as AIDS and patients undergoing immunosuppressive antibiotic treatments. It is critical to understand the host immune response to C. albicans to combat these opportunistic infections. The innate immune system plays an important role in detection, control and clearance of fungal pathogens. In this study, we have addressed the role of the NOD-like Receptors NLRP3 and NLRC4 and the pro-inflammatory cytokine IL-1β in host defense against C. albicans. To investigate the role of IL-1 and inflammasomes in a common opportunistic infection caused by C. albicans, called ‘oropharyngeal candidiasis’ (OPC), we used a clinical strain (GDH2346) isolated from a patient with OPC. Our studies using formalin fixed prep of this strain showed robust processing and release of IL-1β in human as well as mouse immune cells. Being a dimorphic pathogen that occurs in different morphological forms such as yeast, germ-tube or hyphal stages, we observed the germ-tube forms of C. albicans to be more immunostimulatory. Importantly, we demonstrate that C. albicans induced IL-1β production is strictly dependent on the phagocytosis of the fungus and the NLRP3 inflammasome and its associated components, ASC and caspase-1. In addition to NLRP3, NLRC4/IPAF also forms an inflammasome capable of activating caspase-1 and IL-1β cleavage in response to intracellular pathogens. We found that C. albicans induced IL-1β