嗜神经病毒躲避宿主先天性免疫反应的机制和应用培训课件.ppt
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1、嗜神经病毒躲避宿主先天性免疫反应的机制和应用,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,Rabies virus,180nm x 75nm,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,2,Rabies virus180nm x 75nm嗜神经病毒躲,Robert Hurt-USC,Rabies pathogenesis,Patients die of circulatory insufficiency, cardiac arrest and respiratory failure.,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,3,Robert Hurt-USCRabies pathog
2、en,4,Rabies infection and innate immunity,Wang et al. Journal of Virology, 2005,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,4,4Rabies infection and innate i,5,Zhao et al. Journal of Virology, 2009,重组狂犬病病毒构建,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,5,5Zhao et al. Journal of Virolo,6,Expression of MIP-1 attenuated RABV pathogenicity, while
3、 expression of RANTES or IP-10 increased RABV pathogencity,Zhao et al. Journal of Virology, 2009,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,6,6Expression of MIP-1 attenuat,7,Control rHEP HEP-MIP1a HEP-RANTES HEP-IP10,D3D6D9,HE staining of mouse brains,Zhao et al. Journal of Virology, 2009,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,7,7Cont
4、rol rHEP,Expression of MIP-1 enhances VNA production and protection,Zhao et al. Journal of Virology, 2010,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,8,Expression of MIP-1 enhances,Zhao et al. Journal of Virology, 2010,外周过量表达MIP-1会吸引更多的树突状细胞和B细胞,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,9,Zhao et al. Journal of Virolog,嗜神经病毒躲避宿主先天性免疫反应的机制
5、和应用,10,嗜神经病毒躲避宿主先天性免疫反应的机制和应用10,Coronaviruses cause diseases in humans and domestic animals,Adapted from Holmes and Lai, Fields Virology,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,11,Antigenic GroupVirusHostDisea,Why MHV?,MHV produces a broad spectrum of disease in the mouse -pneumonia (MHV-1) -hepatitis (MHV-A59) -enc
6、ephalitis (MHV-A59/JHM) -demylination (MHV-A59)It provides excellent small animal models for hepatitis, for SARS, and for multiple sclerosis,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,12,Why MHV?MHV produces a broad s,Part I: MHV ns2 interferes type I interferon responses,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,13,Part I: MHV ns2 inter
7、feres t,Mutation of ns2 confers attenuation of hepatitis but not CNS disease,IC 500PFU,IH 500PFU,Roth-Cross, J.K. et al, JVI, 2009, 83(8):3743-3753.,brain,liver,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,14,Mutation of ns2 confers atten,Ns2 is an organ specific virulence factor,2H phosphodiesterase; 2 predicted catalyt
8、ic His-x-Thr/Ser motifs (Mazumder et a., 2002; Snijder et al.,2003),(Mazumbder et al., 2002Snijder et al.,2003; Roth-Cross, 2009),嗜神经病毒躲避宿主先天性免疫反应的机制和应用,15,Ns2 is an organ specific virul,Mutation of ns2 confers attenuation of replication in macrophages and microglia but not in other cell types,Zhao,
9、 L. et al, JVI, 2011.Oct; 85(19):10058-10068.,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,16,Mutation of ns2 confers attenu,MOI 1,MOI 0.01,ns2 mutants recover the ability to replicate efficiently in macrophages and microglia from IFNAR knockout mice,MOI 1,Zhao, L. et al, JVI, 2011.Oct; 85(19):10058-10068.,嗜神经病毒躲避宿主先天性免疫
10、反应的机制和应用,17,MOI 1MOI 0.01 ns2 mutants reco,Type 1 interferon induction and signaling pathways,IFN-,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,18,Type 1 interferon induction an,L2,Astro,BMM,IFNAR-/- BMM,ns2 mutants are not defective in induction of IFN-/ mRNA,Both wt RA59 and ns2 mutants induce minimal amounts of IFN-,
11、mRNA in L2 cells and astrocytes,wt RA59 and ns2 mutants induce similar levels of IFN-, mRNA in BMM from both B6 and IFNAR-/- mice,Zhao, L. et al, JVI, 2011.Oct; 85(19):10058-10068.,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,19,L2AstroBMMIFNAR-/- BMMns2 muta,BMM,BMM,Microglia,ns2 mutants are more sensitive to the antivi
12、ral effects of IFN-/ than wt A59 in macrophages and microglia,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,20,BMMBMMMicroglians2 mutants are,Viral replication and IFN sensitivity in the hepatocytes,No IFN,IFN,嗜神经病毒躲避宿主先天性免疫反应的机制和应用,21,Viral replication and IFN sens,In vivo macrophage depletion,Liposomes, encapsulating th
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