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.
|Wang, Tingting; Pan, Deng; Zhou, Zhicheng et al. (2016) Dectin-3 Deficiency Promotes Colitis Development due to Impaired Antifungal Innate Immune Responses in the Gut. PLoS Pathog 12:e1005662|
|Li, Xun; Cullere, Xavier; Nishi, Hiroshi et al. (2016) PKC-? activation in neutrophils promotes fungal clearance. J Leukoc Biol 100:581-8|
|Lee, Ellen J; Brown, Brieanna R; Vance, Emily E et al. (2016) Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye. J Immunol 196:3148-58|
|Atif, Shaikh M; Lee, Seung-Joo; Li, Lin-Xi et al. (2015) Rapid CD4+ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9. Eur J Immunol 45:513-24|
|Drummond, Rebecca A; Collar, Amanda L; Swamydas, Muthulekha et al. (2015) CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System. PLoS Pathog 11:e1005293|
|Jhingran, Anupam; Kasahara, Shinji; Shepardson, Kelly M et al. (2015) Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection. PLoS Pathog 11:e1004589|
|Blonska, Marzenna; Joo, Donghyun; Nurieva, Roza I et al. (2013) Activation of the transcription factor c-Maf in T cells is dependent on the CARMA1-IKK? signaling cascade. Sci Signal 6:ra110|
|Liu, Xikui; Li, Hongxiu; Zhong, Bo et al. (2013) USP18 inhibits NF-?B and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. J Exp Med 210:1575-90|
|Zhu, Le-Le; Zhao, Xue-Qiang; Jiang, Changying et al. (2013) C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection. Immunity 39:324-34|
|Kingeter, Lara M; Lin, Xin (2012) C-type lectin receptor-induced NF-?B activation in innate immune and inflammatory responses. Cell Mol Immunol 9:105-12|