医学免疫学课件：Ebola近期免疫研究进展

1、Ebola近期免疫研究进展目录背景1.1 基本介绍1.2 流行病学1.3 病毒生活史病理学机制2.1 病毒入侵与NPC1蛋白2.2 病理学因素2.3 凝血出血并发成因免疫逃逸机制研究回顾3.1 VP35介导细胞信号感受的抑制3.2 拮抗干扰素介导的信号传递3.3 sGP在免疫逃逸机制中的作用疫苗研发相关回顾未来思考背景1.1 基本介绍丝状病毒科Ebolavirus, Marburgvirus and Cuevavirus在埃博拉病毒的种内有五种亚型: Zaire ebolavirus (now known as EBOV), Sudan ebolavirus (SUDV), Bundibugy

2、o ebolavirus (BDBV), Tai Forest ebolavirus (TAFV) Reston ebolavirus (RESTV).EBOV: 截至2015年9月16日，WHO通报了28200例确诊或疑似患者，其中11291人死亡流行病学相关背景Marc-Antoine de La Vega,Gary Wong,Gary P. Kobinger,Xiangguo Qiu The Multiple Roles of sGP in Ebola Pathogenesis VIRAL IMMUNOLOGY Volume 28, Number 1, 2015GPsGPRNA-depe

3、ndent RNA polymerase病毒入侵病毒入侵主要：巨噬细胞和树突细胞少量感染单核细胞NPC1:protein NiemannPick C1 Carette,J.E. etal. Ebola virus entry requires the cholesterol transporter NiemannPick C1. Nature 477, 340343 (2011).病理学过程细胞因子风暴interleukin1 (IL1), IL6, IL8, IL10, monocyte chemo attractant protein1 (MCP1; also known as CCL2)

4、, macrophage inflammatory protein1 (MIP1; also known as CCL3), MIP1 (also known as CCL4) tumour necrosis factor (TNF),nitric oxide (NO)免疫应答衰退 树突细胞和巨噬细胞死亡，影响体液细胞免疫 CD4+ Tcells, CD8+ Tcells natural killer (NK) cells apoptosis内皮细胞受损出血凝血过程Geisbert,T.W. etal. Mechanisms underlying coagulation abnormaliti

5、es in Ebola hemorrhagic fever:overexpression of tissue factor in primate monocytes/macrophages is a key event. J.Infect. Dis. 188, 16181629 (2003).VP35介导细胞信号感受的抑制protein activator of the IFNinduced antiviral kinase protein kinaseR123VP35蛋白结构特征相关Leung,D.W. etal. Structure of the Ebola VP35 interferon

6、 inhibitory domain. Proc. Natl Acad. Sci. USA 106, 411416 (2009).dsRNA捕获域IIDeVP24/ mVP40阻遏干扰素信号传递信号转导及转录激活蛋白 Zhang,A.P. etal. The Ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold. PLoS Pathog. 8, e1002550 (2012). Xu,W. etal. Ebola virus VP24 targets a uniqu

7、e NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16, 187200 (2014).GP拮抗tetherin促使病毒出芽 Jouvenet,N. etal. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J.Virol. 83, 18371844 (2009).Neil

8、,S.J., Sandrin,V., Sundquist,W.I. & Bieniasz,P.D. An interferon-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host Microbe 2, 193203 (2007).sGP在免疫逃逸机制中的作用sGP作为诱饵抗原误导免疫应答sGP可能参与破坏免疫系统功能Marc-Antoine de La Vega,Gary Wong,Gary P. Kobinger,Xiangguo Qiu The Multiple Roles of sGP in Ebola Pathogenesis VIRAL IMMUNOLOGY Volume 28, Number 1, 2015疫苗相关研发VSV-vaccine10天100%的防护率Interim results from a phase 3 Ebola vaccine study in Guine