The role of CLEC9A in response to M.tuberculosis

• Main Authors: An-Chieh Cheng, 鄭安捷
• Other Authors: Ping-Hui Tseng
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/933393

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 106 === Tuberculosis caused by Mycobacteria tuberculosis is one of the fetal human infectious diseases. Recently, the treatment of Mycobacterium tuberculosis is mainly based on 4-6 months of antibiotics, but there are still problems, such as the ineffective treatment of multiple drug-resistant tuberculosis (MDR-TB). Therefore, it is important to understand the interaction between Mycobacterium and the host immune system. Mycobacteria have a thicker cell wall than other bacteria and the cell wall is associated with its pathogenicity by the specific glycans composition. It has been known in the literature that pattern recognition receptors (PRRs), including toll-like receptors (TLRs)、NOD-like receptors (NLRs) and C type lectin receptors (CLRs) in macrophages and dendritic cells can trigger the release of cytokines and initiate innate immunity by recognizing pathogen-associated molecular patterns (PAMP) on mycobacteria, and then modulate adaptive immunity. Because the mycobacterial surface is covered with glycoproteins and glycolipids, CLRs are critical receptors in mycobacteria recognition. It is still unclear the mechanism how CLRs synergistically regulate the host immunity, and we wanted to identify novel C-type lectins and investigate how they regulate the host immune response. By in vitro lectin binding assay, we find that CLEC9A is a novel C-type lectin interacting with mycobacteria. The data showed that the silencing CLEC9A-expressing cells stimulated with the heat-killed Mycobacteria H37Ra the production of CXCL8 and IL-1through Syk and MAPK signaling pathways The results can be confirmed by using the CLEC9A.Fc fusion protein to block the interaction between mycobacteria and CLEC9A. CLEC9A-mediated signals further affect the migration and activation of neutrophils by modulating CXCL8 and IL-1production. In mouse model, blocking the interaction of CLEC9A with mycobacteria by CLEC9A.Fc fusion protein leads to reduce lung inflammation and immune cell infiltration. In conclusion, during mycobacterial infection, CLEC9A modulates the immune response through specific cytokines and become a potential therapeutic target in the future.