Candida albicans infection is the most common cause of fungal infections, especially, for the expanding population of immuno-suppressed patients, and has become one of leading causes of hospital-acquired blood stream infections. It is estimated that about 40% of affected individuals will die of this disease. The high morbidity and mortality associated with disseminated candidiasis are mainly due to the lack of early and accurate diagnostic tools, the limited anti-fungal drugs, and the emergence of drug resistance. Thus, many studies have investigated the mechanisms of host immunity against this organism and tried to develop alternative immune-based strategies to combat candidiasis. Emerging evidence indicates that several mammalian C-type lectin receptors (CLRs) function as pattern recognition receptors (PRRs) for sensing fungal infections. In our preliminary studies, we have found that Dectin-3 (originally named as CLECSF8/Clec4d), a previously uncharacterized CLR, functions as a PRR for sensing Candida albicans infection. Interestingly, our preliminary data suggest that Dectin-3 forms a heterodimeric complex with Dectin-2, a previously characterized PRR for sensing C. albicans infection. These heterodimeric complexes display a significantly higher sensitivity for detecting C. albicans infection than their respective homodimers, which initiates strong signaling transduction events leading to activation of NF-kB and inflammations. Based on our preliminary studies, we propose 1) to provide the genetic evidence demonstrating that Dectin-3 functions as a key pattern recognition receptor (PRR) for sensing Candida albicans infection, and determine how Dectin-3-mediated innate immune responses impacts on anti-fungal infection;2) to determine how Dectin-3 and Dectin-2 synergistically sense fungal infection;3) to determine how Dectin-3 initiates intracellular signaling, and how this signaling i negatively down-regulated following stimulation. Together, these lines of investigation will reveal molecular mechanism of host innate immune system sensing C. albicans infection, which will provide the molecular basis for designing adjuvant and vaccine against C. albicans infection.
Candida albicans infection is a life-threatening fungal disease for immunocompromised individuals. Revealing the mechanism by which the host immune system detects and clears Candida albicans infection will provide the molecular basis for developing immune-based strategies to combat candidiasis. The proposed studies in this application will identify receptors that sense Candida albicans infection, which will have a significant impact for designing immunological adjuvant and vaccine against C. albicans infection.
