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武汉大学章晓联教授在凝集素Ficolin-2及其相关研究上取得系列突破
at :2017/9/21 18:30:44    

纤维胶凝蛋白(Ficolin)属于补体凝集素,是重要的天然免疫分子。作为可溶性模式识别受体(pattern recognition receptor, PRR),Ficolin能识别病原微生物表面的病原相关模式分子(pathogen-associated molecular pattern, PAMP),并能与甘露糖结合凝集素(Mannose-binding lectin, MBL)相关丝氨酸蛋白酶(MBL-ssociated serine proteases, MASPs)结合而激活补体凝集素途径,还能作为调理素与吞噬细胞表面受体结合而介导调理吞噬作用。

 

武汉大学基础医学院免疫学系章晓联教授研究团队,多年来聚焦Ficolin-2蛋白,不断推进Ficolin-2的科学研究前沿。发现Ficolin-2能够抵抗伤寒杆菌和结核分枝杆菌感染,抑制HCV、HBV、HIV以及A型流感病毒的感染,还具有抗肿瘤效应,并参与了炎症性肠病等病理过程。研究成果涵盖:

 

1. Ficolin-2能结合人型毒性结核分枝杆菌表面的糖脂ManLAM,抑制结核分枝杆菌侵袭靶细胞。Ficolin-2通过活化JNK磷酸化通路,上调细胞因子IFN-g、IL-17、TNF-a以及活性分子NO分泌,发挥抗结核作用(PLoS One 2013)(图一)。Ficolin-A基因敲除小鼠对毒性结核分枝杆菌H37Rv感染表现出更高的易感性)。这些发现将为未来ficolin作为对抗TB的新型免疫治疗分子提供新的治疗手段。

图一 Ficolin-2在结核分枝杆菌感染过程所起作用的模式假说。

 

2. Ficolin-2通过结合HCV包膜糖蛋白E1和E2的糖链导致补体凝集素活化,抑制HCV的早期感染(Cell Mol Immunol 2009)(图二)。Ficolin-2竞争性抑制HCV包膜糖蛋白与其细胞受体LDLR和SRBI的结合,阻断HCV对易感细胞的入侵,而HCV病毒颗粒中的ApoE3可通过竞争性结合HCV-E2抑制Ficolin-2的抗HCV感染效应,促进HCV感染,介导病毒免疫逃逸,该成果发表在免疫学专业权威杂志J Immunol (2014),被Faculty of 1000 Prime列为推荐文章,并被MDLinx作为亮点文章介绍。

图二 载脂蛋白ApoE3通过阻断ficolin-2和HCV-E2之间的相互作用,促进HCV感染并抑制ficolin-2介导的抗病毒活性。

 

3. 通过大量临床样品研究,首次发现慢性乙肝和慢性丙肝患者血清Ficolin-2水平显著上升,且与炎症程度、抗病毒治疗的疗效密切相关,提示其表达上调与HBV和HCV早期控制有关(Scand J Immunol 2013;Virol Sin 2015)。首次报道了Ficolin-2抗HIV-1感染的作用:HIV-1感染能诱导Ficolin-2的表达水平升高,Ficolin-2能与HIV包膜蛋白 gp120结合,阻断HIV感染,并诱导补体依赖的细胞毒作用(Virol Sin 2016)(图三)。Ficolin-2还能通过与流感病毒的血细胞凝集素(Hemagglutinin, HA)和(Neuraminidase, NA)结合抑制流感病毒感染(J Innate Immun 2012)。

图三 Ficolin-2通过与人类免疫缺陷病毒(HIV)包膜糖蛋白gp120的N-聚糖识别从而结合HIV并抑制HIV感染T细胞。

 

4. 在炎症性肠病患者血清中,Ficolin-2水平显著升高,且Ficolin-2水平与患者疾病炎症程度及C反应蛋白水平呈正相关。在小鼠急性结肠炎模型中,Ficolin-A/2 缺失可明显缓解DSS诱导的小鼠急性肠炎,Ficolin-A/2可通过活化 TLR4/MyD88/MAPK/NF-kB信号通路调节巨噬细胞M1极化及炎症因子分泌,进而促进炎症性肠病的发生发展(Immunology 2017)(图四)

图四 Ficolin-A基因敲除小鼠表现出更温和的疾病症状。

 

5. 多种肿瘤病人血清中的Ficolin-2含量下降,在小鼠荷瘤模型中,Ficolin-2/A能有效抵抗肿瘤细胞的生长,并招募更多的M1型巨噬细胞和CD8+T细胞到肿瘤组织中。Ficolin-2能与巨噬细胞表面TLR4结合,促进M0型巨噬细胞和M2型巨噬细胞向M1型巨噬细胞分化,促进巨噬细胞释放细胞因子(IL-6, IFN-g和TNF-a)和NO,Ficolin-2还能促进巨噬细胞和DC抗原递呈能力(Clin Immunol 2017)(图五)

图五 Ficolin-2抑制肿瘤机制的暂定模式。

 


章晓联教授Ficolin-2相关研究SCI论文列表:

1.Ding Q, Shen Y, Li D, Yang J, Yu J, Yin Z, Zhang XL. Ficolin-2 triggers antitumor effect by activating macrophages and CD8+ T cells. Clin Immunol. 2017 Aug 26;183:145-157. doi: 10.1016/j.clim.2017.08.012. [Epub ahead of print]

2.Yang YF, Zhou YD, Hu JC, Luo FL, Xie Y, Shen YY, Bian WX, Yin ZN, Li HL, Zhang XL. Ficolin-A/2, acting as a new regulator of macrophage polarization, mediates the inflammatory response in experimental mouse colitis. Immunology. 2017 Aug;151(4):433-450. doi: 10.1111/imm.12741.

3.Luo F, Chen T, Liu J, Shen X, Zhao Y, Yang R, Zhang X. Ficolin-2 binds to HIV-1 gp120 and blocks viral infection. Virol Sin. 2016 Oct;31(5):406-414.

4.Chen T, Hu Y, Ding Q, Yu J, Wang F, Luo F, Zhang XL. Serum ficolin-2 concentrations are significantly changed in patients with hepatitis B virus infection and liver diseases. Virol Sin. 2015 Aug;30(4):249-60. doi: 10.1007/s12250-015-3605-4.

5.Zhao Y, Ren Y, Zhang X, Zhao P, Tao W, Zhong J, Li Q, Zhang XL. Ficolin-2 inhibits hepatitis C virus infection, whereas apolipoprotein E3 mediates viral immune escape. J Immunol. 2014 Jul 15;193(2):783-96. doi: 10.4049/jimmunol.1302563.

6.Ren Y, Ding Q, Zhang X. Ficolins and infectious diseases. Virol Sin. 2014 Feb;29(1):25-32. doi: 10.1007/s12250-014-3421-2.

7.Luo F, Sun X, Wang Y, Wang Q, Wu Y, Pan Q, Fang C, Zhang XL. Ficolin-2 defends against virulent Mycobacteria tuberculosis infection in vivo, and its insufficiency is associated with infection in humans. PLoS One. 2013 Sep 9;8(9):e73859. doi: 10.1371/journal.pone.0073859.

8.Hu YL, Luo FL, Fu JL, Chen TL, Wu SM, Zhou YD, Zhang XL. Early increased ficolin-2 concentrations are associated with severity of liver inflammation and efficacy of anti-viral therapy in chronic hepatitis C patients. Scand J Immunol. 2013 Feb;77(2):144-50. doi: 10.1111/sji.12014.

9.Pan Q, Chen H, Wang F, Jeza VT, Hou W, Zhao Y, Xiang T, Zhu Y, Endo Y, Fujita T, Zhang XL. L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo. J Innate Immun. 2012;4(3):312-24. doi: 10.1159/000335670.

10.Liu J, Ali MA, Shi Y, Zhao Y, Luo F, Yu J, Xiang T, Tang J, Li D, Hu Q, Ho W, Zhang X. Specifically binding of L-ficolin to N-glycans of HCV envelope glycoproteins E1 and E2 leads to complement activation. Cell Mol Immunol. 2009 Aug;6(4):235-44. doi: 10.1038/cmi.2009.32.

11.Zhang XL, Ali MA. Ficolins: structure, function and associated diseasesAdv Exp Med Biol. 2008;632:105-15. Review. PMID: 19025118.

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