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1、嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用Rabies virus180nm x 75nm嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用2Rabies virus180nm x 75nm嗜神經(jīng)病毒躲Robert Hurt-USCRabies pathogenesisPatients die of circulatory insufficiency, cardiac arrest and respiratory failure.嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用3Robert Hurt-USCRabies pathogen4Rabies in
2、fection and innate immunityWang et al. Journal of Virology, 2005嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用44Rabies infection and innate i5Zhao et al. Journal of Virology, 2009重組狂犬病病毒構(gòu)建嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用55Zhao et al. Journal of Virolo6Expression of MIP-1 attenuated RABV pathogenicity, while expression of RANTES or I
3、P-10 increased RABV pathogencityZhao et al. Journal of Virology, 2009嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用66Expression of MIP-1 attenuat7Control rHEP HEP-MIP1a HEP-RANTES HEP-IP10D3D6D9 HE staining of mouse brainsZhao et al. Journal of Virology, 2009嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用77Control rHEP Expression of MIP-1 enhances
4、 VNA production and protectionZhao et al. Journal of Virology, 2010嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用8Expression of MIP-1 enhancesZhao et al. Journal of Virology, 2010外周過(guò)量表達(dá)MIP-1會(huì)吸引更多的樹(shù)突狀細(xì)胞和B細(xì)胞嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用9Zhao et al. Journal of Virolog嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用10嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用10 Antigenic GroupVi
5、rusHostDiseaseI229ENL63humanhumanrespiratory infectionrespiratory infection, croupTGEVpigrespiratory and enteric infectionCCVdogenteric infectionFECVcatenteric infectionFIPVcatrespiratory,enteric, hepatitis and neurological infectionIIOC43humanRespiratory and possibly enteric infectionSARS-CoVHKU1hu
6、manhumanRespiratoryRespiratoryMHVmouseRespiratory, enteric, neurologic infectionHEVpigRespiratory, enteric, neurologic infectionBCVcowEnteric infectionTCVturkeyRespiratory and enteric infection IIIIBVchickenRespiratory and enteric infection, hepatitisCoronaviruses cause diseases in humans and domest
7、ic animalsAdapted from Holmes and Lai, Fields Virology嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用11 Antigenic GroupVirusHostDiseaWhy MHV?MHV produces a broad spectrum of disease in the mouse -pneumonia (MHV-1) -hepatitis (MHV-A59) -encephalitis (MHV-A59/JHM) -demylination (MHV-A59)It provides excellent small animal mode
8、ls for hepatitis, for SARS, and for multiple sclerosis嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用12Why MHV?MHV produces a broad sPart I: MHV ns2 interferes type I interferon responses 嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用13Part I: MHV ns2 interferes tMutation of ns2 confers attenuation of hepatitis but not CNS disease IC 500PFUIH 500P
9、FU Roth-Cross, J.K. et al, JVI, 2009, 83(8):3743-3753.brainliver嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用14Mutation of ns2 confers attenNs2 is an organ specific virulence factor 1a1b2a45a5bHESEMINMHV 2H phosphodiesterase; 2 predicted catalytic His-x-Thr/Ser motifs (Mazumder et a., 2002; Snijder et al.,2003)ns2(Mazumbd
10、er et al., 2002Snijder et al.,2003; Roth-Cross, 2009)嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用15Ns2 is an organ specific virulMutation of ns2 confers attenuation of replication in macrophages and microglia but not in other cell types Zhao, L. et al, JVI, 2011.Oct; 85(19):10058-10068. 嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用16Mutation o
11、f ns2 confers attenuMOI 1MOI 0.01 ns2 mutants recover the ability to replicate efficiently in macrophages and microglia from IFNAR knockout miceMOI 1 Zhao, L. et al, JVI, 2011.Oct; 85(19):10058-10068. 嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用17MOI 1MOI 0.01 ns2 mutants recoType 1 interferon induction and signaling pat
12、hwaysIFN-IFNTYK2JAK1PSTAT1P STAT1 orSTAT2IFNAR1IFNAR2ISREIRF9PSTAT1PSTAT2 ISGF3PSTAT2IRF-9ISGs:OAS, MxA, ISG15, ISG54,MDA5TLR3TLR7/8TLR9dsRNACpGssRNATIRTBK-1IKK-IRF-3IFN-NF-BATF-2RIG-ICBPPMDA5TIRTIRTRIFMyD88MyD88ISREIFN-嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用18Type 1 interferon induction anL2AstroBMMIFNAR-/- BMMns2
13、mutants are not defective in induction of IFN-/ mRNABoth wt RA59 and ns2 mutants induce minimal amounts of IFN-, 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. 嗜神經(jīng)病毒躲
14、避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用19L2AstroBMMIFNAR-/- BMMns2 mutaBMMBMMMicroglians2 mutants are more sensitive to the antiviral effects of IFN-/ than wt A59 in macrophages and microgliabut not in other cell typesL2Astro嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用20BMMBMMMicroglians2 mutants areViral replication and IFN sensitivity in the
15、 hepatocytesNo IFNIFN嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用21Viral replication and IFN sensIn vivo macrophage depletionLiposomes, encapsulating the Clodronate molecules (squares), are ingested by macrophages via endocytosis. After fusion with lysosomes (L) containing phospholipases (arrowheads), the latter disrupt
16、the bilayers of the liposomes. The more concentric bilayers are disrupted, the greater is the Clodronate release within the cell. The cells are killed by Clodronate through apoptosis. 嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用22In vivo macrophage depletionLiLiposome ClodronateA59ns2-H126RA59ns2-H126RPBSLiposome Clodron
17、ateH&E stainingN protein stainingns2 mutants replicate and induce hepatitis in macrophage depleted mice500 fold vs 10 fold嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用23Liposome ClodronateA59ns2-H126嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用培訓(xùn)課件Part I: conclusionsns2 is an organ specific virulence factor and antagonizes IFN signalingns2 is r
18、equired for replication in macrophages; depletion of macrophages in vivo promotes ns2 mutant virus replicationwe suggest that MHV has to replicate in Kupffer cells in the liver sinusoids in order to reach the liver parenchyma and induce hepatitis 嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用25Part I: conclusions嗜神經(jīng)病毒躲避宿主先
19、天Type 1 interferon induction and signaling pathwaysIFN-IFNTYK2JAK1PSTAT1P STAT1 orSTAT2IFNAR1IFNAR2ISREIRF9PSTAT1PSTAT2 ISGF3PSTAT2IRF-9ISGs:OAS, MxA, ISG15, ISG54,MDA5TLR3TLR7/8TLR9dsRNACpGssRNATIRTBK-1IKK-IRF-3IFN-NF-BATF-2RIG-ICBPPMDA5TIRTIRTRIFMyD88MyD88ISREIFN-嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用26Type 1 int
20、erferon induction anpCAGGS-IFNNS2a-IFNSV5V-IFNNDV-bioassay in Vero cellspCAGGS-no IFNTansfection of pCAGGSor pCAGGS-ns2 or pCAGGS-SV5Vin Vero cellsTreatment with or w/o1000U/ml for 16hInfection of NDV-GFP24h12hGFP 嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用27pCAGGS-IFNNS2a-IFNSV5V-IFNNDV-ISG screening in KO BMMISG15IFIT
21、1IFIT2PKRRNase L嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用28ISG screening in KO BMMISG15IFPart II: MHV ns2 antagonizes OAS-RNase L pathway嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用29Part II: MHV ns2 antagonizesInterferon signaling modelViral dsRNAMDA5*, RIG-I*IFNAntiviral ISGsOAS*2-5ARNase LCellular and viral RNASmall RNAs2-PDEns2?Main pa
22、thwayOAS-RNase L pathwayOAS= 2,5-oliogoadenylate synthetase2-PDE= 2 phosphodiesterase2-5A=2,5oligoadenylate嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用30Interferon signaling modelViraWild type A59 replication in BMM was not affected by the OAS-RNase L system嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用31Wild type A59 replication in BDefective
23、replication of ns2 mutant is restored in RNase L-/- BMMBut not in PKR-/- BMMZhao, L et al. Cell Host & Microbe, 2012, (11) 607616.嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用32Defective replication of ns2 mns2 expression in 293T cellspCAGGS-ns2pCAGGSpCAGGS-ns2-H126RZhao, L et al. Cell Host & Microbe, 2012, (11) 607616.嗜神
24、經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用33ns2 expression in 293T cellspCns2 prevents rRNA cleavage and 2-5A production in BMMZhao, L et al. Cell Host & Microbe, 2012, (11) 607616.嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用34ns2 prevents rRNA cleavage andOverexpression of ns2 in 293T cells prevents rRNA cleavage and 2-5A production induced by poly I:CZhao, L et al. Cell Host & Microbe, 2012, (11) 607616.嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用35Overexpression of ns2 in 293T Ns2 cleaves 2-5A into ATP and AMPZhao, L et al. Cell Host & Microbe, 2012, (11) 607616.嗜神經(jīng)病毒躲避宿主先天性免疫反應(yīng)的機(jī)制和應(yīng)用36Ns2 cleaves 2-5A into ATP and Ns2 enhances
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