Candida albicans is the predominant species of human fungal infections and a common colonizer of the oral cavity in healthy adults, yet pathogenic overgrowth can occur when host immunity is altered due to severe illness or immunosuppression. Recent studies from our group have established a critical role for the pro- inflammatory cytokine IL-1? in protection from oral infection in a model of mucosal candidiasis. The synthesis, processing and release of IL-1? is tightly regulated and require at least two distinct stimuli; first, an inflammatory stimulus mediatd by innate pattern recognition receptors such as TLR2 or dectin-1 causes accumulation of large intracellular stores of pro-IL-1?. A second signal is required for activation of a multi- protein complex, the inflammasome, leading to the activation of caspase-1 and cleavage of pro-IL-1? to the active mature form. We have previously shown that the NLRP3 inflammasome is crucial for protection against Candida infection. New data from our laboratory show that, in addition to the NLRP3 molecule, another inflammasome protein, NLRC4, is up-regulated in oral mucosal tissues following Candida infection. In the absence of NLRC4, mucosal infection is enhanced. We also showed that the role of NLRC4 in anti-fungal defense is tissue specific, playing a more important role in the mucosa than in inflammatory cells, where the NLRP3 inflammasome is activated. In this proposal, we aim to further interrogate the role of different inflammasomes in mucosal immune responses to fungal infection, investigating the impact of NLRP3 versus NLRC4 activation on other important innate epithelial immune responses, the recruitment inflammatory cells, and the development of downstream adaptive immunity to Candida. Additionally, we aim to determine the molecular mechanism including the role of different fungal cell wall components in inflammasome activation in response to Candida. Due to increasing resistance to antifungal drugs, the development of novel therapeutic strategies designed to prevent or enhance clearance of fungal infection is a priority. This project will advance that goal through detailed characterization of the role of the NLRP3 and NLRC4 inflammasomes in host defense to mucosal candidiasis.
This research is highly relevance to Veterans health. We aim to delineate novel innate immune pathways activated by the fungal pathogen Candida albicans, the leading cause of fungal related morbidity and mortality worldwide, and a common colonizer of adult patients. In addition to causing oropharyngeal candidiasis (OPC, also known as thrush) and denture stomatitis when mucosal overgrowth occurs, C. albicans is the major cause of life-threatening fungal diseases and ranks 4th among all bloodstream and nosocomial infections in the United States. These disorders are reemerging due to emerging resistance to anti-fungal agents, a lack of new drug development and the prevalence of immunosuppressive conditions due to HIV/AIDS and medical conditions such as cancer and organ transplantation.
