Hog-MAPK信号转导通路调控光滑念珠菌氧化应激及致病性的机制研究

Candida glabrata is an opportunistic human fungal pathogen. The innate immune system is the first-line of defense against fungal pathogens. The ability of C. glabrata to tolerate oxidative stress, to survive inside macrophages, can evade the natural immunity, and can cause long-term colonization in a host. To investigate the mechanism of C. glabrata to tolerate oxidative stress, maybe can help prevent C. glabrata infection. In a previous study we found that C. glabrata are more resistant to oxidative stress, and the expression levels of HOG1 (a key gene of the Hog-MAPK pathway) increased in C. glabrata with higher tolerance to oxidative stress. Based on the above fingdings, we predicted that the pathway play an important role in tolerance to oxidative stress. By constructing HOG1 Deletion Mutants using the technology of homologous recombination, we can determine the effect of HOG1 deletion on oxidative stress response by real-time quantitative Polymerase Chain Reaction and the technology of proteomics respectively，and by combining bioinformatics. We can judge the effective role of the Hog-MAPK pathway in the virulence of C. glabrata by co-cultured macrophages and animal models. Therefore, it would have great scientific significance to complete the project for provide a theoretical basis for prevention and control of infection of C. glabrata.

光滑念珠菌是重要的人体致病真菌，天然免疫系统是机体抗真菌感染的第一道防线。光滑念珠菌有耐受免疫细胞氧化应激的能力，从而能够逃避机体天然免疫，长期定植于宿主。进一步探讨光滑念珠菌氧化应激的机制，有助于找到有效遏制该菌感染的方法。本课题组预实验显示，光滑念珠菌对氧化应激有较高的耐受性，且耐受性高的菌株，Hog-MAPK信号转导通路的核心基因HOG1表达增高。基于该发现，我们推测该通路在光滑念珠菌抗氧化应激中发挥重要作用。本课题拟通过基因重组技术构建HOG1基因缺失株，运用实时定量RT-PCR、比较蛋白质组学等手段，结合生物信息学方法探讨该通路信号调控的确切机制；并通过检测已知相关致病基因，结合巨噬细胞共培养、动物实验等方法，探讨该通路对致病性的影响。本项目的完成将为揭示Hog-MAPK信号转导通路在光滑念珠菌氧化应激中的作用，为光滑念珠菌感染的防治提供理论基础。