白念珠菌效应因子和激发因子的鉴定和功能研究有待报道，我们从白念珠菌基因组中预测了62个分泌型富半胱氨酸小蛋白SCPs，选出SCP6和SCP10家族成员，探究它们在白念珠菌与宿主相互作用过程中的功能作用。结果表明SCP6的表达和分泌在白念珠菌感染宿主免疫细胞过程明显上调，并依赖TLR2/TLR4激活宿主免疫应答，产生大量细胞因子和趋化因子，从而保护宿主抵抗白念珠菌感染。SCP10家族有六个成员，营养贫瘠能诱导其表达，推测其在白念珠菌定植于粘膜表面会有功能作用。我们将从如下三个方面开展研究：1、鉴定白念珠菌分泌型SCPs，模拟粘膜表面环境和血液条件分析SCPs的表达和分泌；2、研究SCP6作为激发因子激活宿主免疫系统以抵抗真菌感染的应答机制；3、探索SCP10家族成员作为效应因子保护白念珠菌以逃避宿主的免疫防御。阐明SCP6和SCP10家族成员在真菌与宿主共存或对抗过程中的分子机制。

Candida albicans is the most frequently isolated opportunistic pathogen of humans. It is a prevalent fungal pathogen but also a normal resident in human niches. It can colonize on mucosal surfaces, such as oral cavity, vagina and gut in healthy people, while for those immunocompromised patients, like patients with cancer, AIDS or with organ transplanted, it can be highly pathogenic, causing mucocutaneous candidiasis and serious disseminated infections. While small secreted cysteine-rich featured proteins are widely involved in fungus-plant interaction, such proteins have not been reported in human fungal pathogens yet. In this regard, we sought to identify putative SCPs (small secreted cysteine-rich proteins) in the human fungal pathogen C. albicans, and search for candidates with the potential of shaping host immune response. Through preliminary in silica screening, we selected 62 candidate SCP-encoding genes within the genome of C. albicans. These genes presumably encode small proteins (<300 amino acids) comprising a signal peptide and at least four cysteines. We examined the expression patterns of these SCP-encoding genes during C. albicans infection, in particular upon encountering immune cells. Remarkably, the expression and secretion of SCP6 were highly induced in C. albicans following incubation with mouse bone marrow-derived macrophages (BMDMs). We also examined the expression patterns of these SCP-encoding genes in the growth conditions which mimic human niches, and found that the SCP10 expression was highly induced in nutrient poor media. Interestingly, the SCP10 gene family consists of 6 members sharing high similarities each other, however, the expression patterns of these 6 members are differ when the C. albicans cultured in various media, reflecting the different roles of SCP10 family members. When we use the E. coli purified recombinant SCP6 protein to stimulate the immune cells, and find that the SCP6 can trigger the activation of NF-B and MAPK signaling pathways, leading to the expression of proinflammatory cytokines and chemokines. Further genetic and biochemical analyses reveal that both TLR2 and TLR4 are required for the recognition of SCP6. Our results show that SCP6 represents a novel fungus-derived PAMP for host immune response. Upon invasive infection, C. albicans encounter the hostile conditions, such as low ammonium and rich serum, which are widely present in the bloodstream and various tissue environments, therefore elevating SCP6 expression/secretion accordingly. Following its secretion, SCP6 can be sensed by both TLR2 and TLR4, which are abundantly expressed in macrophages and DCs, leading to the activation of IKK/NF-κB and MAPK/AP-1 pathways, triggering the production of cytokines and chemokines to recruit and activate neutrophils and monocytes for fungal clearance. In this research, our aim will be (1) identification of the secreted SCPs, analyzing the expression patterns of these SCP-encoding genes in the growth conditions which mimic human niches including mucosal surfaces and bloodstream; (2) characterizing the SCP6 as a secreted elicitor to trigger the host immune response, analyzing the activated signaling pathways which protect the host from fungal infection; (3) determining the SCP10 family members as the secreted effectors which required for C. albicans virulence against host immune defenses. Our long-range goal is to understand the molecular mechanisms of elicitor-mediated activation and effector-mediated inhibition of host immunity in fungus-host interaction.