The interferon response circuit_ Induction and suppression by pathogenic viruses

The interferon response circuit:Induction and suppression

by pathogenic viruses

Otto Haller *,Georg Kochs,Friedemann Weber

Abteilung Virologie,Institut fu ¨r Medizinische Mikrobiologie und Hygiene,Universita ¨t Freiburg,D-79008Freiburg,Germany

Received 6September 2005;accepted 10September 2005

Abstract

Type I interferons (IFN-a /h )are potent antiviral cytokines and modulators of the adaptive immune system.They are induced by viral infection

or by double-stranded RNA (dsRNA),a by-product of viral replication,and lead to the production of a broad range of antiviral proteins and immunoactive cytokines.Viruses,in turn,have evolved multiple strategies to counter the IFN system which would otherwise stop virus growth early in infection.Here we discuss the current view on the balancing act between virus-induced IFN responses and the viral counterplayers.D 2005Elsevier Inc.All rights reserved.Contents

Introduction ...............................................................119The amazing power of the interferon system ..............................................120Pathways leading to IFN gene expression ................................................120Classical pathway...........................................................120TLR pathway in plasmacytoid dendritic cells.............................................121IFN receptor signaling ..........................................................122IFN-stimulated gene products with antiviral activity...........................................122Viral interference with cellular IFN responses ..............................................123Concluding remarks and outlook.....................................................125Acknowledgments ............................................................125References ......................

(125)

Introduction

Viral infections in children and young adults are common and generally uneventful.In most instances,the patients recover and either eliminate the virus or incorporate it in a latent or persistent form without further problems.Although viruses are obligate intracellular parasites and rely entirely on the metabolic machinery of the host cell,they usually do not cause much harm.The main reason is that our body is not defenseless but makes use of numerous measures to keep viruses at bay.As we know,the type I interferon system is a major player in antiviral defense against all kinds of viruses.Virus-infected cells synthesize and secrete type I interferons (IFN-a /h )which warn the body of the dangerous intruders.

0042-6822/$-see front matter D 2005Elsevier Inc.All rights reserved.doi:10.1016/j.virol.2005.09.024

Abbreviations:AdV,adenovirus;BDV ,Borna disease virus;BUNV,Bunyamwera virus;CSFV ,classical swine fever virus;DHFV,Dengue hemorrhagic fever virus;EBOV ,Ebola virus;EBV ,Epstein –Barr virus;FLUA V ,influenza A virus;FLUBV ,influenza B virus;HCV ,Hepatitis C virus;HHV-8,human herpes virus 8;HIV ,human immunodeficiency virus;HPV16,human papilloma virus 16;HPV18,human papilloma virus 18;HSV-1,herpes simplex virus 1;JEV ,Japanese encephalitis virus;PV ,Polio virus;RV ,Rabies virus;RSV ,respiratory syncytial virus;RVFV ,Rift valley fever virus;THOV,Thogoto virus;TMEV ,Theiler’s meningoencephalitis virus;VV ,Vaccinia virus;VSV ,vesicular stomatitis virus;WNV ,West Nile virus;YFV ,Yellow fever virus.

*Corresponding author.Fax:+497612036626.

E-mail address:otto.haller@uniklinik-freiburg.de (O.Haller).Virology 344(2006)119–

130

https://www.doczj.com/doc/6a1926994.html,/locate/yviro

Secreted IFNs circulate in the body and cause susceptible cells to express potent antiviral mechanisms which limit further viral growth and spread.IFN was discovered almost50years ago by Isaacs and Lindenmann as a cytokine interfering with virus replication(Isaacs and Lindenmann,1957).Since then,much progress has been made in demonstrating how IFNs are induced and how they work.However,only now we begin to appreciate to what extent viruses modulate the IFN response they evoke in the first place.Clearly,viruses would not be successful pathogens if they had not evolved efficient escape strategies allowing them to suppress IFN production,to down-modulate IFN signaling and to block the action of antiviral effector proteins.It is becoming increasingly clear that the IFN antagonistic properties determine viral virulence to a great extent and may contribute to interspecies transmission of so-called emerging and reemerging viruses.Here,we summarize recent highlights in our understanding of how cells defend themselves against viral intruders and how viruses manage to survive in the face of the powerful IFN system.

The amazing power of the interferon system

The type I IFN system is indispensable for vertebrates to control viral infections.This is best illustrated in knockout mice which are unresponsive to IFN-a/h due to targeted deletions in the type I IFN receptor(Muller et al.,1994).These mice quickly succumb to viral infections despite having a normal adaptive immune system(Bouloy et al.,2001;Bray, 2001;Grieder and V ogel,1999;Hwang et al.,1995;Muller et al.,1994;Ryman et al.,2000;van den Broek et al.,1995). Likewise,humans die of viral disease at an early age if they happen to acquire genetic defects of the IFN system(Dupuis et al.,2003).The importance of type I IFNs is further demonstrated in instances where disruption of a single IFN-effector gene causes a complete loss of innate immunity against a particular type of virus,leading to overwhelming infection and rapid death.A telling case is increased susceptibility to influenza and influenza-like viruses found in inbred mouse strains due to a defect in the IFN-regulated Mx1gene (Lindenmann,1964;Staeheli et al.,1988).Susceptible animals are equipped with the full armament of innate and adaptive immunity with the exception of Mx and resist all sorts of viruses but not orthomyxoviruses(Haller,1981;Haller et al., 1998).Transgenic introduction of mouse or human Mx is sufficient to turn susceptible mice into resistant animals (Arnheiter et al.,1990;Pavlovic et al.,1995).More impor-tantly,constitutive expression of human MxA in an otherwise IFN-non-responsive animal confers full protection,demon-strating the exquisite power of a single effector molecule of the human IFN system in an otherwise susceptible host(Hefti et al.,1999).A single autosomal dominant gene locus,designated Flv/Wnv,is responsible for natural resistance of mice against infection with West Nile virus(WNV)and other flaviviruses (Brinton and Perelygin,2003).The gene was recently identified as Oas1b,a member of a large IFN-regulated gene family encoding2V-5V-oligoadenylate synthetases(2-5OAS) known to play an important role in antiviral defense(Mashimo et al.,2002;Perelygin et al.,2002).As in the case of the Mx GTPase,OAS1b has antiviral activity and directly mediates inhibition of WNV replication(Lucas et al.,2003;Perelygin et al.,2002).In recent years,genetic analysis of innate immune responses has exploded and has generated a wealth of new information,as discussed below.

Pathways leading to IFN gene expression

Induction of type I(a/h)IFN gene expression is tightly regulated.Recent findings suggest that cells make use of two major but distinct cellular signal transduction pathways to sense viruses and activate their type I IFN genes.Most cells of the body including fibroblasts,hepatocytes and conventional dendritic cells(cDCs)use the so-called classical pathway.They have intracellular sensors that,upon infection,detect viral components in the cytoplasm and activate the main interferon regulatory transcription factors IRF-3and NF-kB which in turn transactivate IFN-h gene expression.Infected cells secrete mainly IFN-h as an initial response to infection but switch to IFN-a during the subsequent amplification phase of the IFN response(Marie et al.,1998).In contrast,plasmacytoid dendritic cells(pDCs)use Toll-like receptors(TLRs)expressed on the cell surface or in endosomes to sense extracellular or engulfed viral material.TLR signaling of pDCs primarily involves the adaptor protein MyD88and activates IRF-7which is constitutively expressed in pDCs and serves as a master regulator of IFN-a/h gene expression(Honda et al.,2005b). This cell type predominantly secretes high levels of IFN-a and represents the so-called natural interferon producing cells of the body(Colonna et al.,2002;Diebold et al.,2003).Both pathways play important roles during infection and are presently being fully explored.

Classical pathway

The classical pathway of type I IFN induction is best understood for IFN-h gene expression in fibroblasts(Fig.1). In infected cells,a signaling chain is activated by double-stranded RNA(dsRNA)molecules which are generated as intermediates of viral transcription.Two intracellular RNA helicases,RIG-I(Yoneyama et al.,2004)and MDA5(Andrejeva et al.,2004),act as sentinels for viral dsRNA detection.The two related helicases are apparently non-redundant and seem to function in parallel,having a degree of virus specificity (Yoneyama et al.,2005).RIG-I and MDA5are ubiquitously expressed in most tissues and are inducible by IFNs which allows autocrine and paracrine amplification of the sensing system.A third member of the RIG-I helicase family,LGP2,is a natural inhibitor which presumably masks the viral dsRNA from recognition by RIG-I or MDA5and serves as a negative regulator of IFN gene expression(Rothenfusser et al.,2005; Yoneyama et al.,2005).RIG-I and MDA5both contain two N-terminal caspase-recruiting domain(CARD)-like regions and a C-terminal DExD/H box RNA helicase domain(Andrejeva et al.,2004;Yoneyama et al.,2004).RNA-binding to the helicase domain most likely induces a conformational change which

O.Haller et al./Virology344(2006)119–130 120

enables that CARD domain to interact with CARD-like domains of downstream signaling partners (Kato et al.,2005;Yoneyama et al.,2004).Indeed,one interaction partner has just been identified independently by two groups.The novel protein is required to mediate RIG-I and MDA5signals to downstream factors and is therefore called either IPS-1for ‘‘interferon-h -promoter stimulator 1’’(Kawai et al.,2005)or MA VS for ‘‘mitochondrial antiviral signaling’’molecule (Seth et al.,2005).It is identical to an uncharacterized protein previously recog-nized to be involved in NF-kB promoter activation (Matsuda et al.,2003).IPS-1/MA VS has a CARD-like domain which binds to RIG-I and MDA5and a C-terminal region which interacts with FADD and RIP1which are both involved in NF-kB signaling (Kawai et al.,2005).Surprisingly,IPS-1/MA VS localizes to the outer mitochondrial membrane via a C-terminal transmembrane domain.Membrane association and localization to mitochondria is shown to be essential for function (Seth et al.,2005).These findings are intriguing,as they link IFN production and innate immune responses to mitochondrial activity.It is conceivable that the membrane localization of IPS-1/MAVS is advantageous as it may keep the interacting RNA-sensing helicases close to the viral replication factories which often develop in association with intracellullar membranes.

The downstream molecules interacting with IPS-1/MAVS are not yet known.However,IPS-1/MAVS leads indirectly to activation of the IRF-3kinases (Fig.1)(Kawai et al.,2005;Seth et al.,2005).Two I n B kinase (IKK)-related kinases,IKK (and TANK-binding kinase-1(TBK-1),are known to phos-phorylate the transcription factor IRF-3(Fitzgerald et al.,2003;Sharma et al.,2003).IRF-3is a member of the IFN regulatory factor (IRF)family and plays a central role in the activation of the IFN-h promoter (Lin et al.,1998;Schafer et al.,1998;Wathelet et al.,1998;Weaver et al.,1998;Yoneyama et al.,1998).Phosphorylated IRF-3homodimerizes and moves into

the nucleus where it recruits the transcriptional coactivators p300and CREB-binding protein (CBP)to initiate IFN-h mRNA synthesis (Hiscott et al.,1999;Suhara et al.,2002).In addition,NF-n B and AP-1are recruited in a dsRNA-dependent way (Chu et al.,1999).Together these transcription factors strongly up-regulate IFN-a /h gene expression.This initially produced ‘‘first-wave’’IFN triggers expression of a related factor,IRF-7,which is normally not present in most cells or at best in very low amounts (Sato et al.,2000).Genetic evidence has recently shown that IRF-7is the master regulator of IFN gene expression and that IRF-3most likely cooperates with IRF-7for full activity (Honda et al.,2005b ).IRF-7is activated in the same way as IRF-3(Iwamura et al.,2001;Smith et al.,2001;tenOever et al.,2004)and is responsible for a positive-feedback loop that initiates the synthesis of several IFN-a subtypes as the ‘‘second-wave’’IFNs (Marie et al.,1998;Sato et al.,1998).

Some cells of the hematopoietic system such as cDCs preferentially express TLR3and can sense viral and other dsRNA molecules in the endocytic compartment (Fig 1).Ligand-induced triggering of TLR3by dsRNA proceeds via the adaptor molecule TRIF which bypasses IPS-1/MA VS and directly activates the kinase TBK-1.This RIG-I-independent process also leads to phosphorylation and nuclear translocation of IRF-3and IFN-h gene expression.The main difference is that TLR-3-expressing cells do not need to get infected to produce type I IFNs but can respond to viral RNA from inactivated virus particles or dead cells provided they are taken up in the endosomal compartment (Schulz et al.,2005).TLR pathway in plasmacytoid dendritic cells

pDCs are specialized IFN producers and represent a major source of IFN-a in humans (Colonna et al.,2002).They

sense

Fig.1.Type I IFN induction,signaling and action.Left panel:dsRNA,a characteristic by-product of virus replication,leads to activation of the transcription factors NF-n B,IRF-3and AP-1(not shown).The cooperative action of these factors is required for full activation of the IFN-h promoter.IRF-3is phosphorylated by the kinases IKK (and TBK-1which in turn are activated by the RNA-sensing complex of RIG-I,MDA5and IPS-1/MA VS.A second signaling pathway involves endosomal TLR-3and TRIF.Right panel:Newly synthesized IFN-h binds to the type I IFN receptor (IFNAR)and activates the expression of numerous ISGs via the JAK/STAT pathway.IRF-7amplifies the IFN response by inducing the expression of several IFN-h subtypes.SOCS and PIAS are negative regulators of the JAK-STAT pathway.Mx,ISG20,OAS and PKR are examples of proteins with antiviral activity.For details see text.

O.Haller et al./Virology 344(2006)119–130121

the presence of RNA or DNA viruses by TLRs expressed in endosomes (Beutler,2004;Bowie and Haga,2005).Human pDCs mostly express the TLR9subfamily members TLR7,TLR8and TLR9which recognize viral single-stranded (ss)RNA (TLR7,8)or double-stranded CpG-rich DNA (TLR9),respectively (Iwasaki and Medzhitov,2004).Upon activation,TLR7,8and 9signal through their adaptor molecule MyD88which forms a complex with TRAF6and IRF-7(Fig.2).IRF-7is phosphorylated by IRAK-1,an additional component of this receptor-associated multiprotein complex,and transcriptionally activates multiple IFN-a genes (Iwasaki and Medzhitov,2004;Uematsu et al.,2005).A key difference between pDCs and other cell types is their capacity to constitutively express considerable amounts of IRF-7(Kerkmann et al.,2003;Prakash et al.,2005).IRF-7and also IRF-8are further up-regulated in response to IFN and together generate a positive feed back loop for high IFN-a and IFN-h production (Asselin-Paturel and Trinchieri,2005;Tsujimura et al.,2003).

Another distinguishing feature is the recent finding that ligand-bound TLR-9and presumably also TLR-7/TLR8remain active in the endosomal compartment for a long time period,whereas they are rapidly translocated to lysosomes and degraded in other cell types (Honda et al.,2005a ).It is perhaps not surprising that some viruses which are known to cause

prolonged immunosuppression or immune imbalances should target pDCs and inhibit IFN production induced by the TLR-MyD88-IRF-7pathway (Fig.2),because type I IFNs play a major role in shaping adaptive immune responses,in addition to their function in innate immunity (Le Bon and Tough,2002).Recent examples are measles virus and respiratory syncytial virus which block IFN production in pDCs by an as yet unknown mechanism (Schlender et al.,2005).IFN receptor signaling

The IFN receptor signaling pathway is now firmly established and has appropriately been described in compre-hensive reviews (Samuel,2001;Stark et al.,1998).IFN-h and the multiple IFN-a subspecies activate a common type I IFN receptor (IFNAR)which sends a signal to the nucleus through the so-called JAK-STAT pathway (Fig.1).The STAT proteins are latent cytoplasmic transcription factors which become phosphorylated by the Janus kinases JAK-1and TYK-2.Phosphorylated STAT-1and STAT-2recruit a third factor,IRF-9(or p48),to form a complex known as IFN-stimulated gene factor 3(ISGF-3)which translocates to the nucleus and binds to the IFN-stimulated response element (ISRE)in the promoter region of interferon-stimulated genes (ISGs).Specialized proteins serve as negative regulators and inhibitors of the JAK-STAT pathway.The suppressor of cytokine signaling (SOCS)proteins prevent STAT activation (Kubo et al.,2003)whereas protein inhibitor of activated STAT (PIAS)family members function as small ubiquitin-like modifier (SUMO)E3ligases and inhibit the transcriptional activity of STATs (Shuai and Liu,2005).Interestingly,some of these inhibitors are exploited by viruses to down-regulate IFN action (see below).Of great interest in this context is a recent genetic analysis of Drosophila C virus infection in its natural host Drosophila melanogaster ,because the findings demonstrate for the first time a conserved function of the JAK-STAT signaling pathway in insect antiviral immunity (Dostert et al.,2005).It remains to be seen whether insect viruses possess evasion strategies similar to those found in vertebrate viruses.IFN-stimulated gene products with antiviral activity Type I IFNs activate the expression of several hundred IFN-stimulated genes (ISGs)(de Veer et al.,2001;Der et al.,1998)some of which code for antiviral proteins (Fig.1).To date,three antiviral pathways have been firmly established.These comprise the protein kinase R (PKR)(Williams,1999),the 2-5OAS/RNaseL system (Silverman,1994)and the Mx proteins (Haller and Kochs,2002;Isaacs and Lindenmann,1957).Mx proteins belong to the superfamily of dynamin-like large GTPases and have been discovered as mediators of genetic resistance against orthomyxoviruses in mice.Their importance for host survival following infection with certain RNA viruses has been amply demonstrated (Arnheiter et al.,1996;Hefti et al.,1999;Pavlovic et al.,1995)but their exact mode of action is still unknown.The relevance of the OAS/RNaseL and

PKR

Fig.2.TLR signaling pathway for IFN-a production in plasmacytoid dendritic cells (pDCs).TLR7and TLR8respond to RNA viruses by recognizing ssRNA in endosomes.In contrast,TLR9responds to DNA viruses by recognizing CpG-rich sequences.The receptors transmit their signals through an associated multiprotein complex containing the adaptor protein MyD88and the transcription factor IRF-7.In contrast to most other cells,pDCs constitutively express IRF-7(Kerkmann et al.,2003;Prakash et al.,2005).Some pathogenic viruses interfere with this pathway.See text for details.

O.Haller et al./Virology 344(2006)119–130

122

systems in the IFN response to viral infection is well documented both in tissue culture and animal experiments.In addition,their importance is highlighted by the fact that most viruses have evolved specific mechanisms to counteract their activities(see below).Mice lacking one of these components show increased susceptibility to viral infections(Yang et al., 1995;Zhou et al.,1997).Nevertheless,cells from so-called triple knock-out mice lacking PKR,RNaseL and Mx still exhibit a limited IFN-induced antiviral state,indicating that additional antiviral pathways exist(Zhou et al.,1999). Additional proteins with potentially important antiviral activ-ities are ISG20(Espert et al.,2003),promyelocytic leukemia protein(PML)(Regad et al.,2001),guanylate-binding protein 1(GBP-1)(Anderson et al.,1999),P56(Guo et al.,2000;Hui et al.,2003)and RNA-specific adenosine deaminase1 (ADAR1)(Samuel,2001).P56binds a subunit of the eukaryotic translation initiation factor eIF3and thereby suppresses viral as well as cellular RNA translation(Hui et al.,2003;Wang et al.,2003).Importantly,both P56and ADAR1are able to limit hepatitis C virus(HCV)replication to some degree(Taylor et al.,2005;Wang et al.,2003).

Viral interference with cellular IFN responses

Most viruses need to multiply extensively to establish a solid infection in the newly infected host and to provide an outcrop of progeny virus for host-to-host transmission,or else to secure viral persistence or latency.How can a virus reach this goal in the presence of a powerful innate immune response?The answer is that viruses have learned to cope with the IFN system.Shortly after the discovery that heat-inactivated influenza viruses would induce IFN(Isaacs and Lindenmann,1957),Jean Lindenmann reported that infection of cells with a live influenza virus inhibited the subsequent induction of IFN by an inactivated virus.He called this puzzling phenomenon‘‘inverse interference’’(Lindenmann, 1960).It is now evident that most viruses have evolved means to down-regulate IFN responses.In many cases they use non-structural viral proteins for that purpose which are otherwise non-essential for virus growth.This strategy can be exploited in the laboratory to generate mutant viruses that lack the relevant non-essential proteins.Such viruses still grow in IFN-non-responsive cells or organisms but are highly attenuated in IFN-competent https://www.doczj.com/doc/6a1926994.html,ing such an approach,several laboratories have already successfully produced novel vaccine candidates lacking proteins with IFN-antagonistic activity (Ferko et al.,2004;Talon et al.,2000b;Valarcher et al., 2003).Current genetic analyses of many different viruses are revealing an ever-growing number of IFN-antagonistic proteins that target virtually all components of the IFN system.These IFN antagonists are often multifunctional proteins that interact with multiple viral or host cell components and are involved in regulating many different functions in infected cells.For example the NS1of FLUA V is pleiotropic since it not only binds to and sequesters dsRNA molecules to prevent induction of IFNs(Garcia-Sastre,2001;Garcia-Sastre et al.,1998;Talon et al.,2000a;Wang et al.,2000)but also inhibits the3V end processing of cellular pre-mRNAs,regulates the virus replica-tion cycle and enhances translation initiation of viral mRNAs (Krug et al.,2003).Comprehensive reviews have recently dealt with these issues(Basler and Garcia-Sastre,2002;Conzel-mann,2005;Gale and Foy,2005;Hengel et al.,2005;Weber et al.,2004).Here we will address some general points.

Fig.3illustrates the range of activities mediated by IFN antagonists of various viruses.Only a few examples are listed but they demonstrate several important points.First,viral proteins or functions have been identified that cover the whole spectrum of the IFN response in infected cells.Second,a single viral protein may inhibit quite different components of the IFN induction and signaling cascade.Third,a given virus may display more than one IFN-antagonistic activity targeting different pathways.Good examples are the V proteins of some paramyxoviruses which bind to the dsRNA-sensing helicase MDA5and thereby block induction of IFN(Andrejeva et al., 2004)but also provoke the ubiquitinylation and subsequent degradation of STAT1in a complex reaction(Didcock et al., 1999;Palosaari et al.,2003;Precious et al.,2005;Ulane et al., 2005).The NSs protein of Rift valley fever virus is a major virulence factor(Bouloy et al.,2001)and blocks IFN production by inhibiting the basic cellular transcription machinery(Billecocq et al.,2004;Le May et al.,2004). Surprisingly,it also activates the cellular suppressor of STAT activation,SOCS-1,to impede IFN signaling(Miche`le Bouloy, personal communication).Likewise,HSV-1induces SOCS-3 to down-regulate STAT and JAK phosphorylation(Yokota et al.,2004).Interestingly,the core protein of HCV also appears to activate SOCS-3(Bode et al.,2003),while the NS3/4A protease of HCV inhibits RIG-I signaling and has also the ability to disrupt TLR3signaling by inducing cleavage of the adaptor protein TRIF(Breiman et al.,2005;Foy et al.,2005;Li et al.,2005).The NS3/4A protease is essential to cleave the non-structural proteins from the HCV polyprotein synthesized on intracellular membranes and may also lead to degradation of the membrane-bound cellular IPS1/MA VS complexes.

In many negative-strand RNA viruses,the phosphoprotein P, an essential component of the viral polymerase complex,is the main IFN antagonist.For example,the P protein of Rabies virus prevents IRF-3phosphorylation by TBK-1(Brzozka et al.,2005).Likewise,the P protein(called VP35)of Ebola virus (EBOV)interferes with IRF-3activation(Basler et al.,2003). The P protein of Borna disease virus(BDV)directly binds to TBK-1and reduces its activity(Unterstab et al.,2005).A different strategy to block cellular IRF-3is used by certain herpesviruses.Human herpes virus8(HHV-8),the causative agent of Kaposi sarcoma,displays viral IRF homologues, termed vIRFs,which either mimic their cellular counterparts or exert a dominant-negative effect(Burysek et al.,1999a,1999b; Li et al.,1998;Lubyova et al.,2004;Lubyova and Pitha,2000; Zimring et al.,1998).Finally,a far-reaching approach is used by the large poxviruses.They can afford to express soluble IFN-binding proteins which compete with the cellular receptor for its IFN ligand(Alcami et al.,2000;Symons et al.,1995). These‘‘viroceptors’’neutralize whatever IFN is secreted from cells.They prevent the autocrine IFN amplification loop and–

O.Haller et al./Virology344(2006)119–130123

more importantly –the establishment of an antiviral state also in the non-infected tissue surrounding the IFN-producing cells.A fourth point worth discussing is the fact that the virus-induced IFN response is generated in a cascade-like manner (Fig.3).Therefore,viral proteins blocking one component in this circuit also affect distant signaling or effector molecules,thereby amplifying their inhibitory effect.For example,JAK-STAT inhibitors not only suppress the production of antiviral proteins but also the expression of RIG-I,MDA5,IPS-1/MA VS,IRF-3and IRF-7which are all IFN-inducible proteins.As a consequence,production of the ‘‘second-wave’’IFNs is reduced.This enhanced down-regulation of IFN responses acts against the IFN-activating effect of viral dsRNA molecules which progressively accumulate in infected cells.The end-result is a balance between virus-promoting and virus-inhibit-ing factors which may be optimal for each virus-host relationship.

Interestingly,some lytic viruses causing acute infections have adopted a radical strategy usually not found in non-lytic viruses that persist in the body.Poliovirus,vesicular stomatitis virus (VSV)and some bunyaviruses affect the basic cellular transcription machinery and shut-off host gene transcription (Ahmed et al.,2003;Billecocq et al.,2004;Clark et al.,1993;Le May et al.,2004;Thomas et al.,2004;Weber et al.,2002;Yalamanchili et al.,1996;Yuan et al.,1998).More specifically,the non-structural protein NSs of RVFV has been demonstrated to target the p44component of the cellular transcription factor IIH (TFIIH)which is an essential cofactor of the cellular

RNA

Fig.3.Viral inhibitors of the virus-induced IFN-a /h response loop:Viral gene products interfere with the type I IFN system at all levels.The following viral IFN antagonists are shown in clockwise order:NS1of FLUA V (Garcia-Sastre,2001;Garcia-Sastre et al.,1998;Talon et al.,2000a;Wang et al.,2000),NS1of FLUBV (Dauber et al.,2004),E3L VV (Smith et al.,2001;Xiang et al.,2002),V of paramyxoviruses (Andrejeva et al.,2004),NS3/4A of HCV (Breiman et al.,2005;Foy et al.,2005),VP35of EBOV (Basler et al.,2003),P of RV (Brzozka et al.,2005),P of BDV (Unterstab et al.,in press ),V ,W of Nipah virus (Park et al.,2003;Shaw et al.,2004),NS1/NS2of RSV (Bossert et al.,2003;Spann et al.,2004;Valarcher et al.,2003),leader protein of TMEV (Delhaye et al.,2004;van Pesch et al.,2001),ML of THOV (Hagmaier,2003#89;Jennings,2004#233;Pichlmair,2004#247),NPro of CSFV (La Rocca et al.,2005;Ruggli et al.,2003,2005),vIRF and ORF45of HHV-8(Burysek et al.,1999a,1999b;Li et al.,1998;Lubyova et al.,2004;Lubyova and Pitha,2000;Zhu et al.,2002;Zimring et al.,1998),E6of HPV16(Ronco et al.,1998),BZLF-1of EBV (Hahn et al.,2005),M of VSV (Ahmed et al.,2003;Yuan et al.,1998),3C Pro of PV (Clark et al.,1993;Yalamanchili et al.,1996),NSs of BUNV (Thomas et al.,2004;Weber et al.,2002),NSs of RVFV ,(Billecocq et al.,2004;Bouloy et al.,2001;Le May et al.,2004),B18and B8of VV (Alcami et al.,2000;Symons et al.,1995),JEV ,WNV (Guo et al.,2005;Lin et al.,2004),E6of HPV18(Li et al.,1999),core protein of HCV (Bode et al.,2003;Keskinen et al.,2002;Melen et al.,2004;Miller et al.,2004),HSV-1(Yokota et al.,2004),NSs of RVFV (M.Bouloy,https://www.doczj.com/doc/6a1926994.html,munication),V ,C,N of paramyxoviruses (Andrejeva et al.,2002;Didcock et al.,1999;Garcin et al.,2002,2004;Gotoh et al.,2003;Kato et al.,2001;Kubota et al.,2002;Palosaari et al.,2003;Parisien et al.,2001;Rodriguez et al.,2002,2003;Shaffer et al.,2003;Shaw et al.,2004;Takeuchi et al.,2001),NS4B of DHFV ,WNV ,and YFV (Jones et al.,2005;Munoz-Jordan et al.,2003,2005),E1A AdV (Leonard and Sen,1996;Look et al.,1998),NS5A and E2of HCV (Gale et al.,1998;Taylor et al.,1999),EBER of EBV (Elia et al.,1996),V A of AdV (Kitajewski et al.,1986;Mathews and Shenk,1991),K3L of VV (Davies et al.,1992).Not shown:Tat and TAR of HIV interfere with PKR activation (Gunnery et al.,1990;Roy et al.,1990).g 34.5protein of HSV-1reverts the translational block mediated by PKR (He et al.,1997).NS1of influenza B virus targets the IFN-induced ubiquitin-like modifier ISG15,the significance of which remains to be established (Krug et al.,2003).The M27gene product of mouse

O.Haller et al./Virology 344(2006)119–130

124

polymerase II(RNAP II)(Le May et al.,2004).Likewise,the M protein of VSV inactivates TFIID,another RNAP II cofactor (Yuan et al.,1998).Hence,some viral proteins are suppressors of IFN gene expression through their general inhibitory effect on host gene transcription(Ahmed et al.,2003;Billecocq et al., 2004;Thomas et al.,2004).In addition,as already mentioned, the NSs of RVFV activates SOCS-1and has a more specific but indirect effect on the JAK-STAT pathway.To be effective,NSs should be expressed at very early time points of infection.This task would seem difficult to achieve,because NSs of RVFV is transcribed in an ambisense coding strategy from the comple-mentary anti-sense S segment which needs first to be synthesized in infected cells.However,a recent report finds that such anti-sense S segment RNAs are packaged into infectious virus particles and can be transcribed into NSs mRNA immediately after delivery to the cell cytoplasm.It is suggested that the immediate availability of NSs protein may provide a selective advantage in giving the virus a‘‘head start’’over the innate immune system(Ikegami et al.,2005). Concluding remarks and outlook

The interplay between viruses and the IFN responses of their hosts,as described here,is most likely the result of an evolutionary race between the two genetic systems.The race is ongoing,as emerging viruses compete for new hosts and attempt trans-species transmission causing zoonotic infec-tions,as illustrated by recent outbreaks of SARS-coronavirus, Hendra and Nipah viruses,Ebola and Marburg viruses,or the threat of transmission of H5N1avian influenza viruses to humans.

An emerging virus must overcome the IFN defenses of a foreign host to be successful.There is ample evidence that viral IFN antagonists exhibit a degree of species specificity and are efficient in one species but not another(Bossert and Con-zelmann,2002;Chatziandreou et al.,2004;Parisien et al., 2002;Young et al.,2001).However,adaptations are likely to occur.This is best illustrated in arthropod-borne viruses.They replicate in their blood-feeding arthropod hosts and are then transmitted by bite to vertebrate hosts.To continue the transmission cycle,virus replication in the vertebrate host must proceed in the face of a vigorous IFN response.To succeed,arboviruses have evolved specific viral proteins to counteract the IFN system of the vertebrate host,as illustrated in bunyavirus infections(Bouloy et al.,2001;Weber et al., 2002).As invertebrates do not have equivalent IFN genes, these viral IFN antagonists are most likely an adaptation to the mammalian host,securing virus transmission.Another inter-esting example is Thogoto virus(THOV),an influenza-like virus transmitted by ticks to small rodents and,occasionally, man.Its replication occurs in the cell nucleus and is sensitive to inhibition by IFN-induced mouse Mx1and human MxA GTPases(Haller et al.,1995;Kochs and Haller,1999).The Mx block inhibits a very early step in the viral multiplication cycle that affects primary transcription of the incoming genome.Since the virus cannot transcribe and replicate its genome in the presence of Mx,generation of Mx escape mutants is virtually impossible.Therefore,the prime strategy of THOV is to suppress IFN production in the vertebrate host by virtue of its ML protein and to avoid Mx expression in potential target cells,as recently demonstrated in a mouse model(Jennings et al.,2005;Pichlmair et al.,2004).

Future applications involve the genetic manipulation of viral IFN antagonists for the development of novel candidate vaccines.Viruses with targeted deletions in genes known to code for IFN antagonists are promising candidates for live virus vaccines.They grow well in tissue culture but are highly attenuated in the host organism,due to a robust IFN and immune response.This approach has been pioneered for FLUA V(Ferko et al.,2004;Talon et al.,2000b)and for bovine RSV(Valarcher et al.,2003),and may likewise apply to other viruses.

Another fascinating development is the generation of viruses that may be used as oncolytic agents.Mutations in tumor cells often cripple the IFN system,favoring unhindered proliferation and protection from apoptosis(Stojdl et al.,2000). As a consequence,such cells become vulnerable to virus infection.For example,PKR is switched off in tumor cells due to transformation by p21ras(Mundschau and Faller,1995). Alternatively,defects in translational regulation render tumor cells insensitive to PKR action(Balachandran and Barber, 2004).VSV or wild-type reoviruses are highly sensitive to inhibition by PKR(Balachandran et al.,2000;Strong et al., 1998)and preferentially infect cells which have an inactivated PKR pathway(Balachandran and Barber,2004;Coffey et al., 1998).Therefore,selectivity for tumor cells can be increased using genetically engineered viruses devoid of anti-IFN proteins.Such viruses are unable to infect IFN-competent body cells,but are still capable of efficiently replicating and destroying the IFN-deficient tumor cells.A VSV variant with mutations in the M gene inactivating its IFN-antagonistic capacity was shown to specifically lyse tumors in immuno-competent mice(Stojdl et al.,2003).Similarly,an HSV-1 lacking the gene for the anti-PKR protein g34.5was apathogenic even when administered intracerebrally(Hunter et al.,1999),but it could destroy glioma cells(Mineta et al., 1995).

Our present knowledge of the IFN system and viral countermeasures is still limited.However,a better understand-ing of the intimate interplay between viruses and innate immune defenses will open new avenues for drug design, vaccine development and anti-cancer strategies. Acknowledgments

We thank Peter Staeheli for helpful comments.Our own work described in the text was supported be grants from the Deutsche Forschungsgemeinschaft and by the Land Baden-Wu¨rttemberg.

References

Ahmed,M.,McKenzie,M.O.,Puckett,S.,Hojnacki,M.,Poliquin,L.,Lyles,

D.S.,2003.Ability of the matrix protein of vesicular stomatitis virus to

O.Haller et al./Virology344(2006)119–130125

suppress Beta interferon gene expression is genetically correlated with the inhibition of host RNA and protein synthesis.J.Virol.77(8),4646–4657. Alcami,A.,Symons,J.A.,Smith,G.L.,2000.The vaccinia virus soluble alpha/beta interferon(IFN)receptor binds to the cell surface and protects cells from the antiviral effects of IFN.J.Virol.74(23),11230–11239. Anderson,S.L.,Carton,J.M.,Lou,J.,Xing,L.,Rubin,B.Y.,1999.Interferon-induced guanylate binding protein-1(GBP-1)mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus.Virology 256(1),8–14.

Andrejeva,J.,Young,D.F.,Goodbourn,S.,Randall,R.E.,2002.Degradation of STAT1and STAT2by the V proteins of simian virus5and human parainfluenza virus type2,respectively:consequences for virus replica-tion in the presence of alpha/beta and gamma interferons.J.Virol.76(5), 2159–2167.

Andrejeva,J.,Childs,K.S.,Young,D.F.,Carlos,T.S.,Stock,N.,Goodbourn, S.,Randall,R.E.,2004.The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase,mda-5,and inhibit its activation of the IFN-beta promoter.Proc.Natl.Acad.Sci.U.S.A.101(49),17264–17269. Arnheiter,H.,Skuntz,S.,Noteborn,M.,Chang,S.,Meier,E.,1990.Transgenic mice with intracellular immunity to influenza virus.Cell62(1),51–61. Arnheiter,H.,Frese,M.,Kambadur,R.,Meier,E.,Haller,O.,1996.Mx transgenic mice–animal models of health.Curr.Top.Microbiol.Immunol.

206,119–147.

Asselin-Paturel,C.,Trinchieri,G.,2005.Production of type I interferons: plasmacytoid dendritic cells and beyond.J.Exp.Med.202(4),461–465. Balachandran,S.,Barber,G.N.,2004.Defective translational control facilitates vesicular stomatitis virus oncolysis.Cancer Cell5(1),51–65. Balachandran,S.,Roberts,P.C.,Brown,L.E.,Truong,H.,Pattnaik,A.K., Archer,D.R.,Barber,G.N.,2000.Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection.Immunity13(1), 129–141.

Basler,C.F.,Garcia-Sastre,A.,2002.Viruses and the type I interferon antiviral system:induction and evasion.Int.Rev.Immunol.21(4-5),305–337. Basler,C.F.,Mikulasova,A.,Martinez-Sobrido,L.,Paragas,J.,Muhlberger,E., Bray,M.,Klenk,H.D.,Palese,P.,Garcia-Sastre,A.,2003.The Ebola virus VP35protein inhibits activation of interferon regulatory factor3.J.Virol.

77(14),7945–7956.

Beutler,B.,2004.Inferences,questions and possibilities in Toll-like receptor signalling.Nature430(6996),257–263.

Billecocq,A.,Spiegel,M.,Vialat,P.,Kohl,A.,Weber,F.,Bouloy,M.,Haller, O.,2004.NSs protein of Rift Valley Fever Virus blocks interferon production by inhibiting host gene transcription.J.Virol.78,9798–9806. Bode,J.G.,Ludwig,S.,Ehrhardt,C.,Albrecht,U.,Erhardt,A.,Schaper,F., Heinrich,P.C.,Haussinger,D.,2003.IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3.

FASEB J.17(3),488–490.

Bossert, B.,Conzelmann,K.K.,2002.Respiratory syncytial virus(RSV) nonstructural(NS)proteins as host range determinants:a chimeric bovine RSV with NS genes from human RSV is attenuated in interferon-competent bovine cells.J.Virol.76(9),4287–4293.

Bossert,B.,Marozin,S.,Conzelmann,K.K.,2003.Nonstructural proteins NS1 and NS2of bovine respiratory syncytial virus block activation of interferon regulatory factor3.J.Virol.77(16),8661–8668.

Bouloy,M.,Janzen,C.,Vialat,P.,Khun,H.,Pavlovic,J.,Huerre,M.,Haller, O.,2001.Genetic evidence for an interferon-antagonistic function of rift valley fever virus nonstructural protein NSs.J.Virol.75(3),1371–1377. Bowie,A.G.,Haga,I.R.,2005.The role of Toll-like receptors in the host response to viruses.Mol.Immunol.42(8),859–867.

Bray,M.,2001.The role of the Type I interferon response in the resistance of mice to filovirus infection.J.Gen.Virol.82(Pt6),1365–1373. Breiman,A.,Grandvaux,N.,Lin,R.,Ottone,C.,Akira,S.,Yoneyama,M., Fujita,T.,Hiscott,J.,Meurs,E.F.,2005.Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon.J.Virol.79(7),3969–3978. Brinton,M.A.,Perelygin,A.A.,2003.Genetic resistance to flaviviruses.Adv.

Virus Res.60,43–85.

Brzozka,K.,Finke,S.,Conzelmann,K.K.,2005.Identification of the rabies virus alpha/beta interferon antagonist:phosphoprotein P interferes

with phosphorylation of interferon regulatory factor3.J.Virol.79(12), 7673–7681.

Burysek,L.,Yeow,W.S.,Lubyova,B.,Kellum,M.,Schafer,S.L.,Huang,Y.Q., Pitha,P.M.,1999a.Functional analysis of human herpesvirus8-encoded viral interferon regulatory factor1and its association with cellular interferon regulatory factors and p300.J.Virol.73(9),7334–7342. Burysek,L.,Yeow,W.S.,Pitha,P.M.,1999b.Unique properties of a second human herpesvirus8-encoded interferon regulatory factor(vIRF-2).J.Hum.

Virol.2(1),19–32.

Chatziandreou,N.,Stock,N.,Young, D.,Andrejeva,J.,Hagmaier,K., McGeoch, D.J.,Randall,R.E.,2004.Relationships and host range of human,canine,simian and porcine isolates of simian virus5(parainfluenza virus5).J.Gen.Virol.85(Pt10),3007–3016.

Chu,W.M.,Ostertag,D.,Li,Z.W.,Chang,L.,Chen,Y.,Hu,Y.,Williams,B., Perrault,J.,Karin,M.,1999.JNK2and IKKbeta are required for activating the innate response to viral infection.Immunity11(6),721–731. Clark,M.E.,Lieberman,P.M.,Berk,A.J.,Dasgupta,A.,1993.Direct cleavage of human TATA-binding protein by poliovirus protease3C in vivo and in vitro.Mol.Cell.Biol.13(2),1232–1237.

Coffey,M.C.,Strong,J.E.,Forsyth,P.A.,Lee,P.W.,1998.Reovirus therapy of tumors with activated Ras pathway.Science282(5392),1332–1334. Colonna,M.,Krug,A.,Cella,M.,2002.Interferon-producing cells:on the front line in immune responses against pathogens.Curr.Opin.Immunol.14(3), 373–379.

Conzelmann,K.K.,2005.Transcriptional activation of alpha/beta interferon genes:interference by nonsegmented negative-strand RNA viruses.J.Virol.

79(9),5241–5248.

Dauber,B.,Heins,G.,Wolff,T.,2004.The influenza B virus nonstructural NS1 protein is essential for efficient viral growth and antagonizes beta interferon induction.J.Virol.78(4),1865–1872.

Davies,M.V.,Elroy-Stein,O.,Jagus,R.,Moss,B.,Kaufman,R.J.,1992.The vaccinia virus K3L gene product potentiates translation by inhibiting double-stranded-RNA-activated protein kinase and phosphorylation of the alpha subunit of eukaryotic initiation factor2.J.Virol.66(4),1943–1950. de Veer,M.J.,Holko,M.,Frevel,M.,Walker,E.,Der,S.,Paranjape,J.M., Silverman,R.H.,Williams, B.R.,2001.Functional classification of interferon-stimulated genes identified using microarrays.J.Leukocyte Biol.

69(6),912–920.

Delhaye,S.,van Pesch,V.,Michiels,T.,2004.The leader protein of Theiler’s virus interferes with nucleocytoplasmic trafficking of cellular proteins.J.Virol.78(8),4357–4362.

Der,S.D.,Zhou,A.,Williams,B.R.,Silverman,R.H.,1998.Identification of genes differentially regulated by interferon alpha,beta,or gamma using oligonucleotide arrays.Proc.Natl.Acad.Sci.U.S.A.95(26), 15623–15628.

Didcock,L.,Young,D.F.,Goodbourn,S.,Randall,R.E.,1999.The V protein of simian virus5inhibits interferon signalling by targeting STAT1for proteasome-mediated degradation.J.Virol.73(12),9928–9933. Diebold,S.S.,Montoya,M.,Unger,H.,Alexopoulou,L.,Roy,P.,Haswell, L.E.,Al-Shamkhani,A.,Flavell,R.,Borrow,P.,Reis e Sousa,C.,2003.

Viral infection switches non-plasmacytoid dendritic cells into high interferon producers.Nature424(6946),324–328.

Dostert,C.,Jouanguy,E.,Irving,P.,Troxler,L.,Galiana-Arnoux,D.,Hetru,C., Hoffmann,J.A.,Imler,J.L.,2005.The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of Drosophila.Nat.

Immunol.6(9),946–953.

Dupuis,S.,Jouanguy,E.,Al-Hajjar,S.,Fieschi,C.,Al-Mohsen,I.Z.,Al-Jumaah,S.,Yang,K.,Chapgier,A.,Eidenschenk,C.,Eid,P.,Al Ghonaium,

A.,Tufenkeji,H.,Frayha,H.,Al-Gazlan,S.,Al-Rayes,H.,Schreiber,R.D.,

Gresser,I.,Casanova,J.L.,2003.Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1deficiency.Nat.Genet.33(3), 388–391.

Elia, A.,Laing,K.G.,Schofield, A.,Tilleray,V.J.,Clemens,M.J.,1996.

Regulation of the double-stranded RNA-dependent protein kinase PKR by RNAs encoded by a repeated sequence in the Epstein–Barr virus genome.

Nucleic Acids Res.24(22),4471–4478.

Espert,L.,Degols,G.,Gongora,C.,Blondel,D.,Williams,B.R.,Silverman, R.H.,Mechti,N.,2003.ISG20,a new interferon-induced RNase specific

O.Haller et al./Virology344(2006)119–130 126

for single-stranded RNA,defines an alternative antiviral pathway against RNA genomic viruses.J.Biol.Chem.278(18),16151–16158. Fensterl,V.,Grotheer,D.,Berk,I.,Schlemminger,S.,Vallbracht,A.,Dotzauer,

A.,2005.Hepatitis A virus suppresses RIG-I-mediated IRF-3activation to

block induction of beta interferon.J.Virol.79(17),10968–10977. Ferko,B.,Stasakova,J.,Romanova,J.,Kittel,C.,Sereinig,S.,Katinger,H., Egorov,A.,2004.Immunogenicity and protection efficacy of replication-deficient influenza A viruses with altered NS1genes.J.Virol.78(23), 13037–13045.

Fitzgerald,K.A.,McWhirter,S.M.,Faia,K.L.,Rowe, D.C.,Latz, E., Golenbock,D.T.,Coyle,A.J.,Liao,S.M.,Maniatis,T.,2003.IKKepsilon and TBK1are essential components of the IRF3signaling pathway.Nat.

Immunol.4(5),491–496.

Foy,E.,Li,K.,Sumpter Jr.,R.,Loo,Y.M.,Johnson,C.L.,Wang,C.,Fish, P.M.,Yoneyama,M.,Fujita,T.,Lemon,S.M.,Gale Jr.,M.,2005.

Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling.Proc.Natl.Acad.Sci.U.S.A.102

(8),2986–2991.

Gale Jr.,M.,Foy,E.M.,2005.Evasion of intracellular host defence by hepatitis

C virus.Nature436(7053),939–945.

Gale Jr.,M.J.,Korth,M.J.,Katze,M.G.,1998.Repression of the PKR protein kinase by the hepatitis C virus NS5A protein:a potential mechanism of interferon resistance.Clin.Diagn.Virol.10(2–3),157–162.

Garcia-Sastre,A.,2001.Inhibition of interferon-mediated antiviral responses by Influenza A viruses and other negative-strand RNA viruses.Virology 279(2),375–384.

Garcia-Sastre,A.,Egorov,A.,Matassov,D.,Brandt,S.,Levy,D.E.,Durbin, J.E.,Palese,P.,Muster,T.,1998.Influenza A virus lacking the NS1gene replicates in interferon-deficient systems.Virology252(2),324–330. Garcin,D.,Marq,J.B.,Strahle,L.,le Mercier,P.,Kolakofsky,D.,2002.

All four Sendai Virus C proteins bind Stat1,but only the larger forms also induce its mono-ubiquitination and degradation.Virology295(2), 256–265.

Garcin,D.,Marq,J.B.,Iseni,F.,Martin,S.,Kolakofsky,D.,2004.A short peptide at the amino terminus of the Sendai virus C protein acts as an independent element that induces STAT1instability.J.Virol.78(16), 8799–8811.

Gotoh,B.,Takeuchi,K.,Komatsu,T.,Yokoo,J.,2003.The STAT2activation process is a crucial target of Sendai virus C protein for the blockade of alpha interferon signaling.J.Virol.77(6),3360–3370.

Grieder,F.B.,V ogel,S.N.,1999.Role of interferon and interferon regulatory factors in early protection against Venezuelan equine encephalitis virus infection.Virology257(1),106–118.

Gunnery,S.,Rice,A.P.,Robertson,H.D.,Mathews,M.B.,1990.Tat-responsive region RNA of human immunodeficiency virus1can prevent activation of the double-stranded-RNA-activated protein kinase.Proc.Natl.Acad.Sci.

U.S.A.87(22),8687–8691.

Guo,J.,Hui, D.J.,Merrick,W.C.,Sen,G.C.,2000.A new pathway of translational regulation mediated by eukaryotic initiation factor3.EMBO J.

19(24),6891–6899.

Guo,J.T.,Hayashi,J.,Seeger, C.,2005.West Nile virus inhibits the signal transduction pathway of alpha interferon.J.Virol.79(3), 1343–1350.

Hahn,A.M.,Huye,L.E.,Ning,S.,Webster-Cyriaque,J.,Pagano,J.S.,2005.

Interferon regulatory factor7is negatively regulated by the Epstein–Barr virus immediate-early gene,BZLF-1.J.Virol.79(15),10040–10052. Haller,O.,1981.Inborn resistance of mice to orthomyxoviruses.Curr.Top.

Microbiol.Immunol.92,25–52.

Haller,O.,Kochs,G.,2002.Interferon-induced mx proteins:dynamin-like GTPases with antiviral activity.Traffic3(10),710–717.

Haller,O.,Frese,M.,Rost,D.,Nuttall,P.A.,Kochs,G.,1995.Tick-borne thogoto virus infection in mice is inhibited by the orthomyxovirus resistance gene product Mx1.J.Virol.69(4),2596–2601.

Haller,O.,Frese,M.,Kochs,G.,1998.Mx proteins:mediators of innate resistance to RNA viruses.Rev.Sci.Tech.17(1),220–230.

He,B.,Gross,M.,Roizman,B.,1997.The gamma(1)34.5protein of herpes simplex virus1complexes with protein phosphatase1alpha to dephosphor-ylate the alpha subunit of the eukaryotic translation initiation factor2and

preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase.Proc.Natl.Acad.Sci.U.S.A.94(3),843–848.

Hefti,H.P.,Frese,M.,Landis,H.,Di Paolo, C.,Aguzzi, A.,Haller,O., Pavlovic,J.,1999.Human MxA protein protects mice lacking a functional alpha/beta interferon system against La Crosse virus and other lethal viral infections.J.Virol.73(8),6984–6991.

Hengel,H.,Koszinowski,U.H.,Conzelmann,K.K.,2005.Viruses know it all: new insights into IFN networks.Trends Immunol.26(7),396–401. Hiscott,J.,Pitha,P.,Genin,P.,Nguyen,H.,Heylbroeck,C.,Mamane,Y., Algarte,M.,Lin,R.,1999.Triggering the interferon response:the role of IRF-3transcription factor.J.Interferon Cytokine Res.19(1),1–13. Honda,K.,Ohba,Y.,Yanai,H.,Negishi,H.,Mizutani,T.,Takaoka,A.,Taya,

C.,Taniguchi,T.,2005a.Spatiotemporal regulation of MyD88-IRF-7

signalling for robust type-I interferon induction.Nature434(7036), 1035–1040.

Honda,K.,Yanai,H.,Negishi,H.,Asagiri,M.,Sato,M.,Mizutani,T., Shimada,N.,Ohba,Y.,Takaoka,A.,Yoshida,N.,Taniguchi,T.,2005b.

IRF-7is the master regulator of type-I interferon-dependent immune responses.Nature434(7034),772–777.

Hui, D.J.,Bhasker, C.R.,Merrick,W.C.,Sen,G.C.,2003.Viral stress-inducible protein p56inhibits translation by blocking the interaction of eIF3with the ternary complex eIF2,GTP.Met-tRNAi.J.Biol.Chem.278

(41),39477–39482.

Hunter,W.D.,Martuza,R.L.,Feigenbaum,F.,Todo,T.,Mineta,T.,Yazaki,T., Toda,M.,Newsome,J.T.,Platenberg,R.C.,Manz,H.J.,Rabkin,S.D., 1999.Attenuated,replication-competent herpes simplex virus type1mutant G207:safety evaluation of intracerebral injection in nonhuman primates.

J.Virol.73(8),6319–6326.

Hwang,S.Y.,Hertzog,P.J.,Holland,K.A.,Sumarsono,S.H.,Tymms,M.J., Hamilton,J.A.,Whitty,G.,Bertoncello,I.,Kola,I.,1995.A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.Proc.Natl.Acad.Sci.U.S.A.92(24), 11284–11288.

Ikegami,T.,Wong,S.,Peters,C.J.,Makino,S.,2005.Rift valley fever virus NSs mRNA is transcribed from an incoming anti-viral-sense RNA segment.

J.Virol.79(18),12106–12111.

Isaacs,A.,Lindenmann,J.,1957.Virus interference:I.The interferon.Proc.R.

Soc.Lond.,B Biol.Sci.147(927),258–267.

Iwamura,T.,Yoneyama,M.,Yamaguchi,K.,Suhara,W.,Mori,W.,Shiota,K., Okabe,Y.,Namiki,H.,Fujita,T.,2001.Induction of IRF-3/-7kinase and NF-kappaB in response to double-stranded RNA and virus infection: common and unique pathways.Genes Cells6(4),375–388.

Iwasaki,A.,Medzhitov,R.,2004.Toll-like receptor control of the adaptive immune responses.Nat.Immunol.5(10),987–995.

Jennings,S.,Mart?′nez-Sobrido,L.,Garc?′a-Sastre,A.,Weber,F.,Kochs,G., 2005.Thogoto Virus ML protein suppresses IRF3function.Virology331

(1),63–72.

Jones,M.,Davidson,A.,Hibbert,L.,Gruenwald,P.,Schlaak,J.,Ball,S., Foster,G.R.,Jacobs,M.,2005.Dengue virus inhibits alpha interferon signaling by reducing STAT2expression.J.Virol.79(9),5414–5420. Kato,A.,Ohnishi,Y.,Kohase,M.,Saito,S.,Tashiro,M.,Nagai,Y.,2001.Y2, the smallest of the Sendai virus C proteins,is fully capable of both counteracting the antiviral action of interferons and inhibiting viral RNA synthesis.J.Virol.75(8),3802–3810.

Kato,H.,Sato,S.,Yoneyama,M.,Yamamoto,M.,Uematsu,S.,Matsui,K., Tsujimura,T.,Takeda,K.,Fujita,T.,Takeuchi,O.,Akira,S.,2005.Cell type-specific involvement of RIG-I in antiviral response.Immunity23(1), 19–28.

Kawai,T.,Takahashi,K.,Sato,S.,Coban,C.,Kumar,H.,Kato,H.,Ishii, K.J.,Takeuchi,O.,Akira,S.,2005.IPS-1,an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction.Nat.Immunol., 16127453.

Kerkmann,M.,Rothenfusser,S.,Hornung,V.,Towarowski,A.,Wagner,M., Sarris,A.,Giese,T.,Endres,S.,Hartmann,G.,2003.Activation with CpG-

A and CpG-

B oligonucleotides reveals two distinct regulatory pathways of

type I IFN synthesis in human plasmacytoid dendritic cells.J.Immunol.

170(9),4465–4474.

O.Haller et al./Virology344(2006)119–130127

Keskinen,P.,Melen,K.,Julkunen,I.,2002.Expression of HCV structural proteins impairs IFN-mediated antiviral response.Virology 299(2),164–171.

Kitajewski,J.,Schneider,R.J.,Safer,B.,Munemitsu,S.M.,Samuel,C.E., Thimmappaya,B.,Shenk,T.,1986.Adenovirus V AI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2alpha kinase.Cell45(2),195–200.

Kochs,G.,Haller,O.,1999.Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids.Proc.Natl.Acad.Sci.

U.S.A.96(5),2082–2086.

Krug,R.M.,Yuan,W.,Noah,D.L.,Latham,A.G.,2003.Intracellular warfare between human influenza viruses and human cells:the roles of the viral NS1protein.Virology309(2),181–189.

Kubo,M.,Hanada,T.,Yoshimura,A.,2003.Suppressors of cytokine signaling and immunity.Nat.Immunol.4(12),1169–1176.

Kubota,T.,Yokosawa,N.,Yokota,S.,Fujii,N.,2002.Association of mumps virus V protein with RACK1results in dissociation of STAT-1from the alpha interferon receptor complex.J.Virol.76(24),12676–12682.

La Rocca,S.A.,Herbert,R.J.,Crooke,H.,Drew,T.W.,Wileman,T.E.,Powell, P.P.,2005.Loss of interferon regulatory factor3in cells infected with classical swine fever virus involves the N-terminal protease,Npro.J.Virol.

79(11),7239–7247.

Le Bon,A.,Tough,D.F.,2002.Links between innate and adaptive immunity via type I interferon.Curr.Opin.Immunol.14(4),432–436.

Le May,N.,Dubaele,S.,De Santis,L.P.,Billecocq,A.,Bouloy,M.,Egly,J.M., 2004.TFIIH transcription factor,a target for the Rift Valley hemorrhagic fever virus.Cell116(4),541–550.

Leonard,G.T.,Sen,G.C.,1996.Effects of adenovirus E1A protein on interferon-signaling.Virology224(1),25–33.

Li,M.,Lee,H.,Guo,J.,Neipel,F.,Fleckenstein,B.,Ozato,K.,Jung,J.U., 1998.Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor.J.Virol.72(7),5433–5440.

Li,S.,Labrecque,S.,Gauzzi,M.C.,Cuddihy,A.R.,Wong,A.H.,Pellegrini,S., Matlashewski,G.J.,Koromilas,A.E.,1999.The human papilloma virus (HPV)-18E6oncoprotein physically associates with Tyk2and impairs Jak-STAT activation by interferon-alpha.Oncogene18(42),5727–5737.

Li,K.,Foy,E.,Ferreon,J.C.,Nakamura,M.,Ferreon,A.C.,Ikeda,M.,Ray, S.C.,Gale Jr.,M.,Lemon,S.M.,2005.Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor3adaptor protein TRIF.Proc.Natl.Acad.Sci.U.S.A.102(8),2992–2997.

Lin,R.,Heylbroeck, C.,Pitha,P.M.,Hiscott,J.,1998.Virus-dependent phosphorylation of the IRF-3transcription factor regulates nuclear translocation,transactivation potential,and proteasome-mediated degrada-tion.Mol.Cell.Biol.18(5),2986–2996.

Lin,R.J.,Liao,C.L.,Lin,E.,Lin,Y.L.,2004.Blocking of the alpha interferon-induced Jak-Stat signaling pathway by Japanese encephalitis virus infection.J.Virol.78(17),9285–9294.

Lindenmann,J.,1960.Interferon und inverse Interferenz.Zeitschr.Hygiene 146,287–309.

Lindenmann,J.,1964.Inheritance of Resistance to Influenza Virus in Mice.

Proc.Soc.Exp.Biol.Med.116,506–509.

Look,D.C.,Roswit,W.T.,Frick,A.G.,Gris-Alevy,Y.,Dickhaus,D.M.,Walter, M.J.,Holtzman,M.J.,1998.Direct suppression of Stat1function during adenoviral infection.Immunity9(6),871–880.

Lubyova,B.,Pitha,P.M.,2000.Characterization of a novel human herpesvirus 8-encoded protein,vIRF-3,that shows homology to viral and cellular interferon regulatory factors.J.Virol.74(17),8194–8201.

Lubyova, B.,Kellum,M.J.,Frisancho, A.J.,Pitha,P.M.,2004.Kaposi’s sarcoma-associated herpesvirus-encoded vIRF-3stimulates the transcrip-tional activity of cellular IRF-3and IRF-7.J.Biol.Chem.279(9), 7643–7654.

Lucas,M.,Mashimo,T.,Frenkiel,M.P.,Simon-Chazottes,D.,Montagutelli, X.,Ceccaldi,P.E.,Guenet,J.L.,Despres,P.,2003.Infection of mouse neurones by West Nile virus is modulated by the interferon-inducible2V-5V oligoadenylate synthetase1b protein.Immunol.Cell Biol.81(3),230–236. Marie,I.,Durbin,J.E.,Levy,D.E.,1998.Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7.EMBO J.17(22),6660–6669.Mashimo,T.,Lucas,M.,Simon-Chazottes,D.,Frenkiel,M.P.,Montagutelli, X.,Ceccaldi,P.E.,Deubel,V.,Guenet,J.L.,Despres,P.,2002.A nonsense mutation in the gene encoding2V-5V-oligoadenylate synthetase/L1isoform is associated with West Nile virus susceptibility in laboratory mice.Proc.Natl.

Acad.Sci.U.S.A.99(17),11311–11316.

Mathews,M.B.,Shenk,T.,1991.Adenovirus virus-associated RNA and translation control.J.Virol.65,5657–5662.

Matsuda,A.,Suzuki,Y.,Honda,G.,Muramatsu,S.,Matsuzaki,O.,Nagano,Y., Doi,T.,Shimotohno,K.,Harada,T.,Nishida,E.,Hayashi,H.,Sugano,S., https://www.doczj.com/doc/6a1926994.html,rge-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.Oncogene22(21), 3307–3318.

Melen,K.,Fagerlund,R.,Nyqvist,M.,Keskinen,P.,Julkunen,I.,2004.

Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs.J.Med.Virol.73(4),536–547.

Miller,K.,McArdle,S.,Gale Jr.,M.J.,Geller,D.A.,Tenoever,B.,Hiscott,J., Gretch,D.R.,Polyak,S.J.,2004.Effects of the hepatitis C virus core protein on innate cellular defense pathways.J.Interferon Cytokine Res.24(7), 391–402.

Mineta,T.,Rabkin,S.D.,Yazaki,T.,Hunter,W.D.,Martuza,R.L.,1995.

Attenuated multi-mutated herpes simplex virus-1for the treatment of malignant gliomas.Nat.Med.1(9),938–943.

Muller,U.,Steinhoff,U.,Reis,L.F.,Hemmi,S.,Pavlovic,J.,Zinkernagel, R.M.,Aguet,M.,1994.Functional role of type I and type II interferons in antiviral defense.Science264(5167),1918–1921.

Mundschau,L.J.,Faller, D.V.,1995.Platelet-derived growth factor signal transduction through the interferon-inducible kinase PKR.Immediate early gene induction.J.Biol.Chem.270(7),3100–3106.

Munoz-Jordan,J.L.,Sanchez-Burgos,G.G.,Laurent-Rolle,M.,Garcia-Sastre,

A.,2003.Inhibition of interferon signaling by dengue virus.Proc.Natl.

Acad.Sci.U.S.A.100(24),14333–14338.

Munoz-Jordan,J.L.,Laurent-Rolle,M.,Ashour,J.,Martinez-Sobrido,L., Ashok,M.,Lipkin,W.I.,Garcia-Sastre,A.,2005.Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses.J.Virol.79(13), 8004–8013.

Palosaari,H.,Parisien,J.P.,Rodriguez,J.J.,Ulane,C.M.,Horvath,C.M.,2003.

STAT protein interference and suppression of cytokine signal transduction by measles virus V protein.J.Virol.77(13),7635–7644.

Parisien,J.P.,Lau,J.F.,Rodriguez,J.J.,Sullivan,B.M.,Moscona,A.,Parks,

G.D.,Lamb,R.A.,Horvath, C.M.,2001.The V protein of human

parainfluenza virus2antagonizes type I interferon responses by destabiliz-ing signal transducer and activator of transcription2.Virology283(2), 230–239.

Parisien,J.P.,Lau,J.F.,Horvath,C.M.,2002.STAT2acts as a host range determinant for species-specific paramyxovirus interferon antagonism and simian virus5replication.J.Virol.76(13),6435–6441.

Park,M.S.,Shaw,M.L.,Munoz-Jordan,J.,Cros,J.F.,Nakaya,T.,Bouvier,N., Palese,P.,Garcia-Sastre,A.,Basler,C.F.,2003.Newcastle disease virus (NDV)-based assay demonstrates interferon-antagonist activity for the NDV V protein and the Nipah virus V.W,and C proteins.J.Virol.77(2), 1501–1511.

Pavlovic,J.,Arzet,H.A.,Hefti,H.P.,Frese,M.,Rost,D.,Ernst,B.,Kolb,E., Staeheli,P.,Haller,O.,1995.Enhanced virus resistance of transgenic mice expressing the human MxA protein.J.Virol.69(7),4506–4510. Perelygin,A.A.,Scherbik,S.V.,Zhulin,I.B.,Stockman,B.M.,Li,Y.,Brinton, M.A.,2002.Positional cloning of the murine flavivirus resistance gene.

Proc.Natl.Acad.Sci.U.S.A.99(14),9322–9327.

Pichlmair,A.,Buse,J.,Jennings,S.,Haller,O.,Kochs,G.,Staeheli,P.,2004.

Thogoto virus lacking interferon-antagonistic protein ML is strongly attenuated in newborn Mx1-positive but not Mx1-negative mice.J.Virol.

78,11422–11424.

Prakash,A.,Smith,E.,Lee,C.K.,Levy,D.E.,2005.Tissue-specific positive feedback requirements for production of type I interferon following virus infection.J.Biol.Chem.280(19),18651–18657.

Precious,B.,Young,D.F.,Andrejeva,L.,Goodbourn,S.,Randall,R.E.,2005.

In vitro and in vivo specificity of ubiquitination and degradation of STAT1 and STAT2by the V proteins of the paramyxoviruses simian virus5and human parainfluenza virus type2.J.Gen.Virol.86(Pt1),151–158.

O.Haller et al./Virology344(2006)119–130 128

Regad,T.,Saib,A.,Lallemand-Breitenbach,V.,Pandolfi,P.P.,de The,H., Chelbi-Alix,M.K.,2001.PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral transactivator.Embo J.20(13),3495–3505.

Rodriguez,J.J.,Parisien,J.P.,Horvath, C.M.,2002.Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2activation and nuclear accumulation.J.Virol.76(22), 11476–11483.

Rodriguez,J.J.,Wang,L.F.,Horvath,C.M.,2003.Hendra virus V protein inhibits interferon signaling by preventing STAT1and STAT2nuclear accumulation.J.Virol.77(21),11842–11845.

Ronco,L.V.,Karpova, A.Y.,Vidal,M.,Howley,P.M.,1998.Human papillomavirus16E6oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity.Genes Dev.12(13),2061–2072. Rothenfusser,S.,Goutagny,N.,DiPerna,G.,Gong,M.,Monks, B.G., Schoenemeyer,A.,Yamamoto,M.,Akira,S.,Fitzgerald,K.A.,in press.

The RNA helicase Lgp2inhibits TLR-independent sensing of viral replication by RIG-I.J.Immunol.

Roy,S.,Katze,M.G.,Parkin,N.T.,Edery,I.,Hovanessian,A.G.,Sonenberg, N.,1990.Control of the interferon-induced68-kilodalton protein kinase by the HIV-1tat gene product.Science247(4947),1216–1219.

Ruggli,N.,Tratschin,J.D.,Schweizer,M.,McCullough,K.C.,Hofmann,M.A., Summerfield,A.,2003.Classical swine fever virus interferes with cellular antiviral defense:evidence for a novel function of N(pro).J.Virol.77(13), 7645–7654.

Ruggli,N.,Bird,B.H.,Liu,L.,Bauhofer,O.,Tratschin,J.D.,Hofmann,M.A., 2005.N(pro)of classical swine fever virus is an antagonist of double-stranded RNA-mediated apoptosis and IFN-alpha/beta induction.Virology. Ryman,K.D.,Klimstra,W.B.,Nguyen,K.B.,Biron,C.A.,Johnston,R.E., 2000.Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism.J.Virol.

74(7),3366–3378.

Samuel,C.E.,2001.Antiviral actions of interferons.Clin.Microbiol.Rev.14

(4),778–809.

Sato,M.,Hata,N.,Asagiri,M.,Nakaya,T.,Taniguchi,T.,Tanaka,N.,1998.

Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7.FEBS Lett.441(1),106–110.

Sato,M.,Suemori,H.,Hata,N.,Asagiri,M.,Ogasawara,K.,Nakao,K., Nakaya,T.,Katsuki,M.,Noguchi,S.,Tanaka,N.,Taniguchi,T.,2000.

Distinct and essential roles of transcription factors IRF-3and IRF-7in response to viruses for IFN-alpha/beta gene induction.Immunity13(4), 539–548.

Schafer,S.L.,Lin,R.,Moore,P.A.,Hiscott,J.,Pitha,P.M.,1998.Regulation of type I interferon gene expression by interferon regulatory factor-3.J.Biol.

Chem.273(5),2714–2720.

Schlender,J.,Hornung,V.,Finke,S.,Gunthner-Biller,M.,Marozin,S., Brzozka,K.,Moghim,S.,Endres,S.,Hartmann,G.,Conzelmann,K.K., 2005.Inhibition of toll-like receptor7-and9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus.J.Virol.79(9),5507–5515.

Schulz,O.,Diebold,S.S.,Chen,M.,Naslund,T.I.,Nolte,M.A.,Alexopoulou, L.,Azuma,Y.T.,Flavell,R.A.,Liljestrom,P.,Reis e Sousa,C.,2005.Toll-like receptor3promotes cross-priming to virus-infected cells.Nature433 (7028),887–892.

Seth,R.B.,Sun,L.,Ea,C.K.,Chen,Z.J.,2005.Identification and Character-ization of MA VS,a Mitochondrial Antiviral Signaling Protein that Activates NF-kappaB and IRF3.Cell,16125763.

Shaffer,J.A.,Bellini,W.J.,Rota,P.A.,2003.The C protein of measles virus inhibits the type I interferon response.Virology315(2),389–397. Sharma,S.,TenOever,B.R.,Grandvaux,N.,Zhou,G.P.,Lin,R.,Hiscott,J., 2003.Triggering the interferon antiviral response through an IKK-related pathway.Science300,1148–1151.

Shaw,M.L.,Garcia-Sastre,A.,Palese,P.,Basler,C.F.,2004.Nipah virus V and W proteins have a common STAT1-binding domain yet inhibit STAT1 activation from the cytoplasmic and nuclear compartments,respectively.

J.Virol.78(11),5633–5641.

Shuai,K.,Liu,B.,2005.Regulation of gene-activation pathways by PIAS proteins in the immune system.Nat.Rev.,Immunol.5(8),593–605.Silverman,R.H.,1994.Fascination with2-5A-dependent RNase:a unique enzyme that functions in interferon action.J.Interferon Res.14(3), 101–104.

Smith, E.J.,Marie,I.,Prakash, A.,Garcia-Sastre, A.,Levy, D.E.,2001.

IRF3and IRF7phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by vaccinia virus E3L protein.J.Biol.Chem.276(12), 8951–8957.

Spann,K.M.,Tran,K.C.,Chi,B.,Rabin,R.L.,Collins,P.L.,2004.Suppression of the induction of alpha,beta,and gamma interferons by the NS1and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages.J.Virol.78(8),4363–4369.

Spiegel,M.,Pichlmair,A.,Martinez-Sobrido,L.,Cros,J.,Garcia-Sastre,A., Haller,O.,Weber,F.,2005.Inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor3.J.Virol.79(4),2079–2086. Staeheli,P.,Grob,R.,Meier,E.,Sutcliffe,J.G.,Haller,O.,1988.Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation.Mol.Cell.Biol.8(10),4518–4523.

Stark,G.R.,Kerr,I.M.,Williams,B.R.,Silverman,R.H.,Schreiber,R.D.,1998.

How cells respond to interferons.Annu.Rev.Biochem.67,227–264. Stojdl,D.F.,Lichty,B.,Knowles,S.,Marius,R.,Atkins,H.,Sonenberg,N., Bell,J.C.,2000.Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.Nat.Med.6(7),821–825. Stojdl, D.F.,Lichty, B.D.,tenOever, B.R.,Paterson,J.M.,Power, A.T., Knowles,S.,Marius,R.,Reynard,J.,Poliquin,L.,Atkins,H.,Brown,

E.G.,Durbin,R.K.,Durbin,J.E.,Hiscott,J.,Bell,J.C.,2003.VSV strains

with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents.Cancer Cell4(4),263–275.

Strong,J.E.,Coffey,M.C.,Tang, D.,Sabinin,P.,Lee,P.W.,1998.The molecular basis of viral oncolysis:usurpation of the Ras signaling pathway by reovirus.EMBO J.17(12),3351–3362.

Suhara,W.,Yoneyama,M.,Kitabayashi,I.,Fujita,T.,2002.Direct involvement of CREB-binding protein/p300in sequence-specific DNA binding of virus-activated interferon regulatory factor-3holocomplex.J.Biol.Chem.277

(25),22304–22313.

Symons,J.A.,Alcami,A.,Smith,G.L.,1995.Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity.

Cell81(4),551–560.

Takeuchi,K.,Komatsu,T.,Yokoo,J.,Kato,A.,Shioda,T.,Nagai,Y.,Gotoh,

B.,2001.Sendai virus C protein physically associates with Stat1.Genes

Cells6(6),545–557.

Talon,J.,Horvath,C.M.,Polley,R.,Basler,C.F.,Muster,T.,Palese,P.,Garcia-Sastre,A.,2000a.Activation of interferon regulatory factor3is inhibited by the influenza A virus NS1protein.J.Virol.74(17),7989–7996. Talon,J.,Salvatore,M.,O’Neill,R.E.,Nakaya,Y.,Zheng,H.,Muster,T., Garcia-Sastre,A.,Palese,P.,2000b.Influenza A and B viruses expressing altered NS1proteins:A vaccine approach.Proc.Natl.Acad.Sci.U.S.A.97

(8),4309–4314.

Taylor, D.R.,Shi,S.T.,Romano,P.R.,Barber,G.N.,Lai,M.M.,1999.

Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein.Science285(5424),107–110.

Taylor,D.R.,Puig,M.,Darnell,M.E.,Mihalik,K.,Feinstone,S.M.,2005.New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1.J.Virol.79(10),6291–6298.

tenOever,B.R.,Sharma,S.,Zou,W.,Sun,Q.,Grandvaux,N.,Julkunen,I., Hemmi,H.,Yamamoto,M.,Akira,S.,Yeh,W.C.,Lin,R.,Hiscott,J.,2004.

Activation of TBK1and IKK epsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity.J.Virol.78(19),10636–10649. Thomas,D.,Blakqori,G.,Wagner,V.,Banholzer,M.,Kessler,N.,Elliott, R.M.,Haller,O.,Weber, F.,2004.Inhibition of RNA polymerase II phosphorylation by a viral interferon antagonist.J.Biol.Chem.279, 31471–31477.

Tsujimura,H.,Tamura,T.,Ozato,K.,2003.Cutting edge:IFN consensus sequence binding protein/IFN regulatory factor8drives the development of type I IFN-producing plasmacytoid dendritic cells.J.Immunol.170(3), 1131–1135.

O.Haller et al./Virology344(2006)119–130129

Uematsu,S.,Sato,S.,Yamamoto,M.,Hirotani,T.,Kato,H.,Takeshita,F., Matsuda,M.,Coban,C.,Ishii,K.J.,Kawai,T.,Takeuchi,O.,Akira,S., 2005.Interleukin-1receptor-associated kinase-1plays an essential role for Toll-like receptor(TLR)7-and TLR9-mediated interferon-{alpha}induc-tion.J.Exp.Med.201(6),915–923.

Ulane,C.M.,Kentsis,A.,Cruz,C.D.,Parisien,J.P.,Schneider,K.L.,Horvath,

C.M.,https://www.doczj.com/doc/6a1926994.html,position and assembly of STAT-targeting ubiquitin ligase

complexes:paramyxovirus V protein carboxyl terminus is an oligomeriza-tion domain.J.Virol.79(16),10180–10189.

Unterstab,G.,Ludwig,S.,Anton,A.,Planz,O.,Dauber,B.,Krappmann,D., Heins,G.,Ehrhardt,C.,Wolff,T.,2005.Viral targeting of the interferon-beta inducing Traf family member-associated NF-kB activator-(TANK) binding kinase-1.Proc.Natl.Acad.Sci.U.S.A.102(38),13640–13645. Valarcher,J.F.,Furze,J.,Wyld,S.,Cook,R.,Conzelmann,K.K.,Taylor,G., 2003.Role of alpha/beta interferons in the attenuation and immunogenicity of recombinant bovine respiratory syncytial viruses lacking NS proteins.

J.Virol.77(15),8426–8439.

van den Broek,M.F.,Muller,U.,Huang,S.,Aguet,M.,Zinkernagel,R.M., 1995.Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors.J.Virol.69(8),4792–4796.

van Pesch,V.,van Eyll,O.,Michiels,T.,2001.The leader protein of Theiler’s virus inhibits immediate-early alpha/beta interferon production.J.Virol.75

(17),7811–7817.

Wang,X.,Li,M.,Zheng,H.,Muster,T.,Palese,P.,Beg, A.A.,Garcia-Sastre,A.,2000.Influenza A virus NS1protein prevents activation of NF-kappaB and induction of alpha/beta interferon.J.Virol.74(24), 11566–11573.

Wang,C.,Pflugheber,J.,Sumpter Jr.,R.,Sodora,D.L.,Hui,D.,Sen,G.C., Gale Jr.,M.,2003.Alpha interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication.J.Virol.77(7), 3898–3912.

Wathelet,M.G.,Lin,C.H.,Parekh,B.S.,Ronco,L.V.,Howley,P.M.,Maniatis, T.,1998.Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo.Mol.Cell1(4), 507–518.

Weaver,B.K.,Kumar,K.P.,Reich,N.C.,1998.Interferon regulatory factor3 and CREB-binding protein/p300are subunits of double-stranded RNA-activated transcription factor DRAF1.Mol.Cell.Biol.18(3),1359–1368. Weber,F.,Bridgen,A.,Fazakerley,J.K.,Streitenfeld,H.,Randall,R.E.,Elliott, R.M.,2002.Bunyamwera bunyavirus nonstructural protein NSs counteracts the induction of alpha/beta interferon.J.Virol.76,7949–7955.

Weber et al.,2004.Inverse interference:how viruses fight the interferon system.Viral Immunol.17(4),498–515.

Williams,B.R.,1999.PKR;a sentinel kinase for cellular stress.Oncogene18

(45),6112–6120.

Xiang,Y.,Condit,R.C.,Vijaysri,S.,Jacobs,B.,Williams,B.R.,Silverman, R.H.,2002.Blockade of Interferon Induction and Action by the E3L Double-Stranded RNA Binding Proteins of Vaccinia Virus.J.Virol.76(10), 5251–5259.Yalamanchili,P.,Harris,K.,Wimmer,E.,Dasgupta,A.,1996.Inhibition of basal transcription by poliovirus:a virus-encoded protease(3Cpro)inhibits formation of TBP-TATA box complex in vitro.J.Virol.70(5),2922–2929. Yang,Y.L.,Reis,L.F.,Pavlovic,J.,Aguzzi, A.,Schafer,R.,Kumar, A., Williams,B.R.,Aguet,M.,Weissmann,C.,1995.Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase.EMBO J.

14(24),6095–6106.

Yokota,S.,Yokosawa,N.,Okabayashi,T.,Suzutani,T.,Miura,S.,Jimbow,K., Fujii,N.,2004.Induction of suppressor of cytokine signaling-3by herpes simplex virus type1contributes to inhibition of the interferon signaling pathway.J.Virol.78(12),6282–6286.

Yoneyama,M.,Suhara,W.,Fukuhara,Y.,Fukuda,M.,Nishida,E.,Fujita,T., 1998.Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3and CBP/p300.EMBO J.17(4),1087–1095.

Yoneyama,M.,Kikuchi,M.,Natsukawa,T.,Shinobu,N.,Imaizumi,T., Miyagishi,M.,Taira,K.,Akira,S.,Fujita,T.,2004.The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.Nat.Immunol.5(7),730–737.

Yoneyama,M.,Kikuchi,M.,Matsumoto,K.,Imaizumi,T.,Miyagishi,M., Taira,K.,Foy,E.,Loo,Y.M.,Gale Jr.,M.,Akira,S.,Yonehara,S.,Kato,A., Fujita,T.,2005.Shared and unique functions of the DExD/H-Box helicases RIG-I,MDA5,and LGP2in antiviral innate immunity.J.Immunol.175(5), 2851–2858.

Young,D.F.,Chatziandreou,N.,He,B.,Goodbourn,S.,Lamb,R.A.,Randall, R.E.,2001.Single amino acid substitution in the V protein of simian virus5 differentiates its ability to block interferon signaling in human and murine cells.J.Virol.75(7),3363–3370.

Yuan,H.,Yoza,B.K.,Lyles,D.S.,1998.Inhibition of host RNA polymerase II-dependent transcription by vesicular stomatitis virus results from inactiva-tion of TFIID.Virology251(2),383–392.

Zhou,A.,Paranjape,J.,Brown,T.L.,Nie,H.,Naik,S.,Dong,B.,Chang,A., Trapp,B.,Fairchild,R.,Colmenares,C.,Silverman,R.H.,1997.Interferon action and apoptosis are defective in mice devoid of2V,5V-oligoadenylate-dependent RNase L.EMBO J.16(21),6355–6363.

Zhou,A.,Paranjape,J.M.,Der,S.D.,Williams,B.R.,Silverman,R.H.,1999.

Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways.Virology258(2),435–440.

Zhu,F.X.,King,S.M.,Smith,E.J.,Levy,D.E.,Yuan,Y.,2002.A Kaposi’s sarcoma-associated herpesviral protein inhibits virus-mediated induction of type I interferon by blocking IRF-7phosphorylation and nuclear accumu-lation.Proc.Natl.Acad.Sci.U.S.A.99(8),5573–5578. Zimmermann,A.,Trilling,M.,Wagner,M.,Wilborn,M.,Bubic,I.,Jonjic,S., Koszinowski,U.,Hengel,H.,2005.A cytomegaloviral protein reveals a dual role for STAT2in IFN-{gamma}signaling and antiviral responses.

J.Exp.Med.201(10),1543–1553.

Zimring,J.C.,Goodbourn,S.,Offermann,M.K.,1998.Human herpesvirus 8encodes an interferon regulatory factor(IRF)homolog that represses IRF-1-mediated transcription.J.Virol.72(1),701–707.

O.Haller et al./Virology344(2006)119–130 130

2018届高考文言文翻译之典型例题：2016年高考真题

2018届高考文言文翻译之典型例题：2016年高考真题 2018届高考文言文翻译之典型例题：2016年高考真题 2018届高考文言文翻译之典型例题：2016年高考真题 一、（2016年高考新课标I卷）阅读下面的文言文，完成4～7题。 曾公亮，字明仲，泉州晋江人。举进士甲科，知会稽县。民田镜湖旁，每患湖溢。公亮立斗门，泄水入曹娥江，民受其利。以端明殿学士知郑州，为政有能声盗悉窜他境至夜户不闭尝有使客亡橐中物移书诘盗公亮报吾境不藏盗殆从之者度耳索之果然 公亮明练文法，更践久，习知朝廷台阁典宪，首相韩琦每咨访焉。仁宗末年，琦请建储，与公亮等共定大议。密州民田产银，或盗取之，大理当以强。公亮日：此禁物也，取之虽强，与盗物民家有间矣。固争之，遂下有司议，比劫禁物法，盗得不死。契丹纵人渔界河，又数通盐舟，吏不敢禁，皆谓：与之校，且生事。公亮言：萌芽不禁，后将奈何？雄州赵滋勇而有谋，可任也。使谕以指意，边害讫息。英宗即位，加中书侍郎兼礼部尚书，寻加户部尚书。帝不豫，辽使至不能见，命公亮宴于馆，使者不肯赴。公亮质之曰：锡宴不赴，是不虔君命也。人主有疾，而必使亲临，处之安乎？使者即就席。熙宁三年，拜司空兼侍中、河阳三城节度使。明年，起判永兴军。居一岁，还京师。旋以太傅致仕。元丰元年卒，年八十。帝临哭，辍朝三日。公亮方厚庄重，沉深周密，平居谨绳墨，蹈规矩；然性吝啬，殖货至巨万。初荐王安石，及同辅政，知上方向之，阴为子孙计，凡更张庶事，一切听顺，而外若不与之者。常遣子孝宽参其谋，至上前略无所异，于是帝益信任安石。安石德其助己，故引擢孝宽至枢密以报之。苏轼尝从容责公亮不能救正，世讥其持禄固宠云。 （节选自《宋史曾公亮传》） 7.把文中画横线的句子翻译成现代汉语。 （1）锡宴不赴，是不虔君命也。人主有疾，而必使亲临，处之安乎? 译文：________________________________________________________________ ______________________________________________________________________ （2）苏轼尝从容责公亮不能救正，世讥其持禄固宠云。 译文：________________________________________________________________ ______________________________________________________________________ 二、（2016年高考新课标卷）阅读下面的文言文，完成4～7题。 陈登云，字从龙，唐山人。万历五年进士。除鄢陵知县，征授御史。出按辽东，疏陈安攘十策，又请速首功之赏。改巡山西。还朝，会廷臣方争建储。登云谓议不早决，由贵妃家阴沮之。十六年六月遂因灾异抗疏，劾妃父郑承宪，言：承宪怀祸藏奸窥觊储贰且广结术士之流曩陛下重惩科场冒籍承宪妻每扬言事由己发用以恐喝勋贵簧鼓朝绅 不但惠安遭其虐焰，即中宫与太后家亦谨避其锋矣。陛下享国久长，自由敬德所致，而承宪每对人言，以为不立东宫之效。干挠盛典，蓄隐邪谋，他日何所不至？疏入，贵妃、承宪皆怒，同列亦为登云危，帝竟留中不下。久之，疏论吏部尚书陆光祖，又论贬四川提学副使冯时可，论罢应天巡抚李涞、顺天巡抚王致祥，又论礼部侍郎韩世能、尚书罗万化、南京太仆卿徐用检。朝右皆惮之。时方考选科道，登云因疏言：近岁言官，壬午以前怵于威，则摧刚为柔；壬午以后昵于情，则化直为佞。其间岂无刚直之人，而弗胜龃龉，多不能安其身。二十年来，以刚直擢京卿者百止一二耳。背公植党，逐嗜乞怜，如所谓‘七豺’‘八狗’者，言路顾居其半。夫台谏为天下持是非，而使人贱辱至此，安望其抗颜直绳，为国家锄大奸、歼巨蠹哉！与其误用而斥之，不若慎于始进。因条数事以献。出按河南。岁大饥，人相食。

对翻译中异化法与归化法的正确认识

对翻译中异化法与归化法的正确认识 班级：外语学院、075班 学号：074050143 姓名：张学美 摘要：运用异化与归化翻译方法,不仅是为了让读者了解作品的内容,也能让读者通过阅读译作,了解另一种全新的文化,因为进行文化交流才是翻译的根本任务。从文化的角度考虑,采用异化法与归化法,不仅能使译文更加完美,更能使不懂外语的人们通过阅读译文,了解另一种文化,促进各民族人们之间的交流与理解。翻译不仅是语言符号的转换,更是跨文化的交流。有时,从语言的角度所作出的译文可能远不及从文化的角度所作出的译文完美。本文从翻译策略的角度，分别从不同时期来说明人们对异化法与归化法的认识和运用。 关键词:文学翻译；翻译策略；异化；归化；辩证统一 一直以来,无论是在我国还是在西方,直译(literal translation)与意译(liberal translation)是两种在实践中运用最多,也是被讨论研究最多的方法。1995年,美籍意大利学者劳伦斯-韦努蒂(Lawrence Venuti)提出了归化(domestication)与异化(foreignization)之说,将有关直译与意译的争辩转向了对于归化与异化的思考。归化与异化之争是直译与意译之争的延伸,是两对不能等同的概念。直译和意译主要集中于语言层面,而异化和归化则突破语言的范畴,将视野扩展到语言、文化、思维、美学等更多更广阔的领域。 一、归化翻译法 Lawrwnce Venuti对归化的定义是,遵守译入语语言文化和当前的主流价值观,对原文采用保守的同化手段,使其迎合本土的典律,出版潮流和政治潮流。采用归化方法就是尽可能不去打扰读者,而让作者向读者靠拢(the translator leaves the reader in peace, as much as possible, and moves the author towards him)。归化翻译法的目的在于向读者传递原作的基本精神和语义内容,不在于语言形式或个别细节的一一再现。它的优点在于其流利通顺的语言易为读者所接受,译文不会对读者造成理解上的障碍,其缺点则是译作往往仅停留在内容、情节或主要精神意旨方面,而无法进入沉淀在语言内核的文化本质深处。 有时归化翻译法的采用也是出于一种不得已,翻译活动不是在真空中进行的,它受源语文化和译语文化两种不同文化语境的制约,还要考虑到两种文化之间的

译林版中考英语复习专题 初中英语连词专项练习和答案含答案解析

译林版中考英语复习专题初中英语连词专项练习和答案含答案解析 一、初中英语连词 1．My wallet dropped on the ground ________________ I was walking. A. before B. after C. while D. because 【答案】 C 2．You like football ___________ she likes reading. A. When B. or C. because D. while 【答案】 D 3．You'd better travel around Nanjing with a local tour guide ______________ you want to know more about its culture. A. unless B. until C. although D. if 【答案】 D 【解析】【分析】句意：如果你想了解南京的文化，最好带着当地的导游游览一下。A：unless除非；B： until 直到……才（为止）；C： although 尽管；D： if如果。导游带领游览是了解南京的条件，因此要用从属连词if，故选D。 【点评】考查连词辨析。理解连词的词义和用法，根据前后句的关系，选择正确的连词。 4．After the new high-speed railway line began operations, the time on the trip from Lianyungang to Qingdao now is much less than __________in the past. A. one B. this C. that D. it 【答案】 C 【解析】【分析】句意：新高速铁路开通后，连云港到青岛的时间比过去少了很多。A：one，一，同类中的一个；B：this（指时间、距离较近或下文要提到的人或事物）这个；C：that，（指时间、距离较远或指上文提到过人或事物）那，那个；D：it它指与上文的同一个。根据 the time on the trip from Lianyungang to Qingdao now，可知是指上文提到过时间，要用that。故选C。 【点评】考查连词辨析。理解选项意思和用法，根据句子的语法结构，选择正确的连词。 5．The film seems interesting ______ we all want to see it. A. and B. but C. unless D. if 【答案】 A 【解析】【分析】句意：这部电影似乎很有趣，我们都想看。A：and又，和，表示顺接； B： but但是，表示转折； C： unless除非。表示条件； D： if如果，表示假设。根据interesting 和want to see，可知前后两句是顺接关系，要用and。 【点评】考查连词辨析。根据前后句的关系，选择正确的连词。 6．Some people waste food___________ others haven't enough.

高中文言文精短翻译练习100道题

高中文言文精短翻译练习100篇 1、范仲淹有志于天下 原文：范仲淹二岁而孤，母贫无靠，再适常山朱氏。既长，知其世家，感泣辞母，去之南都入学舍。昼夜苦学，五年未尝解衣就寝。或夜昏怠，辄以水沃面。往往糜粥不充，日昃始食，遂大通六经之旨，慨然有志于天下。常自诵曰：当先天下之忧而忧，后天下之乐而乐。 翻译：范仲淹二岁的时候死了父亲。母亲很穷，没有依靠。就改嫁到了常山的朱家。（范仲淹）长大以后，知道了自己的生世，含着眼泪告别母亲，离开去应天府的南都学舍读书。（他）白天、深夜都认真读书。五年中，竟然没有曾经脱去衣服上床睡觉。有时夜里感到昏昏欲睡，往往把水浇在脸上。（范仲淹）常常是白天苦读，什么也不吃，直到日头偏西才吃一点东西。就这样，他领悟了六经的主旨，后来又立下了造福天下的志向。他常常自己讲道：“当先天下之忧而忧，后天下之乐而乐。” 2、陈蕃愿扫除天下 原文：藩年十五，尝闲处一室，而庭宇芜岁。父友同郡薛勤来候之，谓藩曰：“孺子何不洒扫以待宾客？”藩曰：“大丈夫处世，当扫除天下，安事一室乎？”勤知其有清世志，甚奇之。 译文：陈藩十五岁的时候，曾经独自住在一处，庭院以及屋舍十分杂乱。他父亲同城的朋友薛勤来拜访他，对他说：“小伙子你为什么不整理打扫房间来迎接客人？”陈藩说：“大丈夫处理事情，应当以扫除天下的坏事为己任。不能在乎一间屋子的事情。”薛勤认为他有让世道澄清的志向，与众不同。 3、班超投笔从戎 原文：班超字仲升，扶风平陵人，徐令彪之少子也。为人有大志，不修细节。然内孝谨，居家常执勤苦，不耻劳辱。有口辩，而涉猎书传。永平五年。兄固被召诣校书郎，超与母随至洛阳。家贫，常为官佣书以供养。久劳苦，尝辍业投笔叹曰：“大丈夫无它志略，犹当效傅介子、张骞立功异域，以取封侯，安能久事笔研间乎？”左右皆笑之。超曰：“小子安知壮士志哉！” 翻译：班超为人有远大的志向，不计较一些小事情。然而在家中孝顺勤谨，过日子常常辛苦操劳，不以劳动为耻辱。他能言善辩，粗览了许多历史典籍。公元62年(永平五年)，哥哥班固被征召做校书郎，班超和母亲也随同班罟到了洛阳。因为家庭贫穷，班超常为官府抄书挣钱来养家。他长期抄写，劳苦不堪，有一次，他停下的手中的活儿，扔了笔感叹道：“大丈夫如果没有更好的志向谋略，也应像昭帝时期的傅介子、武帝时期的张骞那样，在异地他乡立下大功，以得到封侯，怎么能长期地在笔、砚之间忙忙碌碌呢？”旁边的人都嘲笑他，班超说：“小子怎么能了解壮士的志向呢！” 4、宗悫（què）乘风破浪 原文：宗悫字元干，南阳涅阳人也。叔父炳高尚不仕。悫年少时，炳问其志。悫曰：“愿乘长风破万里浪。”炳曰：“汝若不富贵，必破我门户。”兄泌娶妻，始入门，夜被劫，悫年十四，挺身与拒贼，十余人皆披散，不得入室。时天下无事，士人并以文艺为业，炳素高节，诸子群从皆好学，而悫任气好武，故不为乡曲所称。 翻译：宗悫，字元干，是南阳涅阳人。他的叔父宗炳，学问很好但不肯做官。宗悫小的时候，宗炳问他长大后志向是什么？他回答：“希望驾着大风刮散绵延万里的巨浪。”（宗炳说：“就算你不能大富大贵，也必然会光宗耀祖。”）有一次宗悫的哥哥宗泌结婚，结婚的当晚就遭到强盗打劫。当时宗悫才14岁，却挺身而出与强盗打斗，把十几个强盗打得四下溃散，根本进不了正屋。当时天下太平，有点名望的人都认为习文考取功名是正业。宗炳因为学问高，大家都喜欢跟着他读儒家经典。而宗悫因为任性而且爱好武艺，因此不被同乡称赞。 5、祖逖闻鸡起舞 原文：范阳祖逖，少有大志，与刘琨俱为司州主簿，同寝，中夜闻鸡鸣，蹴琨觉曰：“此非恶声也！”因起舞。及渡江，左丞相睿以为军谘祭酒。逖居京口，纠合骁健，言于睿曰：“晋室之乱，非上无道而下怨叛也，由宗室争权，自相鱼肉，遂使戎狄乘隙，毒流中土。今遗民既遭残贼，人思自奋，大王诚能命将出师，使如逖者统之以复中原，郡国豪杰，必有望风响应者矣！”睿素无北伐之志，以逖为奋威将军、豫州刺史，给千人廪，布三千匹，不给铠仗，使自召募。逖将其部曲百余家渡江，中流，击楫而誓曰：“祖逖不能清中原而复济者，有如大江！”遂屯淮阴，起冶铸兵，募得二千余人而后进。 翻译：当初，范阳人祖逖，年轻时就有大志向，曾与刘琨一起担任司州的主簿，与刘琨同寝，夜半时听到鸡鸣，他踢醒刘琨，说：“这不是令人厌恶的声音。”就起床舞剑。渡江以后，左丞相司马睿让他担任军咨祭酒。祖逖住在京口，聚集起骁勇强健的壮士，对司马睿说：“晋朝的变乱，不是因为君主无道而使臣下怨恨叛乱，而是皇亲宗室之间争夺权力，自相残杀，这样就使戎狄之人钻了空子，祸害遍及中原。现在晋朝的遗民遭到摧残伤害后，大家都想着自强奋发，大王您确实能够派遣将领率兵出师，使像我一样的人统领军队来光复中原，各地的英雄豪杰，一定会有闻风响应的人！”司马睿一直没有北伐的志向，他听了祖逖的话以后，就任命祖逖为奋威将军、豫州刺史，仅仅拨给他千人的口粮，三千匹布，不供给兵器，让祖逖自己想办法募集。祖逖带领自己私家的军队共一百多户人家渡过长江，在江中敲打着船桨说：“祖逖如果不能使中原清明而光复成功，就像大江一样有去无回！”于是到淮阴驻扎，建造熔炉冶炼浇铸兵器，又招募了二千多人然后继续前进。 6、画家赵广不屈 原文：赵广，合肥人。本李伯时家小史，伯时作画，每使侍左右。久之遂善画。尤工画马。几能乱真，建炎中陷贼，贼闻其善画，使图所虏妇人，广毅然辞以实不能画，胁以白刃，不从遂断右手拇指遣去，而广平生适用左手。乱定，惟画观音大士而已。又数年，乃死，今士大夫所藏伯时观音，多广笔也。 翻译：赵广是合肥人，本来是李伯时家里的书童。李伯时作画的时候就侍奉在左右，时间长了就擅长画画了，尤其擅长画马，几乎和李伯时所作的一样。建炎年间，他落在金兵手里。金兵听说他擅长画画，就让他画掳来的妇人。赵广毅然推辞作画，金兵用刀子威胁，没得逞，就将他的右手拇指砍去。而赵广其实是用左手作画的。局势平定以后，赵广只画观音大士。又过了几年，赵广死了，如今有地位的知识分子所藏的李伯时的观音画，大多是赵广的手笔。 7、苏武牧羊北海上

译林版中考英语专项训练初中英语连词专项练习题含答案解析

译林版中考英语专项训练初中英语连词专项练习题含答案解析 一、初中英语连词 1．Peter bought some goldfish ______________ he found it difficult to raise them. A. because B. or C. though D. until 【答案】 C 2．My mother has little interest in football ___________ she didn't watch the live match on TV yesterday evening. A. so B. if C. though D. when 【答案】 A 3．The environment will be much worse ______everyone has a sense of protecting it. A. unless B. if C. so that 【答案】 A 【解析】【分析】句意：除非每个人有保护环境的意识，否则环境将会更糟糕。A除非……否则；B如果；C为了。除非有环保意识，否则环境将变得更糟，本句是unless引导的条件状语从句，故答案选A。 【点评】考查连词辨析，首先识记连词词义，然后根据词义和句意确定。 4．— Do you know ____________Grandma is going to visit us？ —Next Saturday. She told me on the phone. A. where B. why C. when D. whether 【答案】 C 【解析】【分析】句意：——你知道奶奶什么时候来看望我们吗？——下周六。她在电话告诉我们的。where 哪里；why 为什么；when 何时；whether是否. 根据答语next Saturday，可知问的是时间，用when提问，故选C。 【点评】本题考查疑问词辨析。根据答语确定所使用的疑问词。 5．—We should work hard. We'll never give up. China dream can come true. —I think so. Let's try our best. A. But B. And C. Or 【答案】 B 【解析】【分析】句意：——我们应该努力学习，我们就将永不放弃，这样中国梦可以实现。——我这样认为。让我们尽我们最大努力。A但是表示转折；B和，表示并列；C或者，表示转折。根据题干可知，句子前后是并列关系，则应用and，故答案选B。 【点评】考查连词辨析，首先识记连词词义，然后根据句意确定。 6．— Would you like to go camping this weekend? — I'd love to, ______________ I can't. I have to prepare for the English Speech Contest.

中考文言文翻译实用方法经典讲解(带试题实例!)

一.增就是增补，在翻译时增补文言文省略句中的省略成分。 注意：补出省略的成分或语句，要加括号。 1、增补原文省略的主语、谓语或宾语 例1：“一鼓作气，再而衰，三而竭。”“再”“三”后省略了谓语“鼓”，翻译时要补上。 例2：“见渔人，乃大惊，问所从来。”译句：“（桃源中人）一见渔人，大为惊奇，问他是从哪里来的。” 例3：“君与具来。”“与”后省略了宾语“之”。 2、增补使语义明了的关联词 例：“不治将益深”是一个假设句，译句：“（如果）不治疗就会更加深入”。 二 .删就是删除，凡是古汉语中的发语词、在句子结构上起标志作用的助词和凑足音节的助词等虚词，因在现代汉语中是没有词能代替，故翻译时无须译出，可删去。 例1：“师道之不传也久矣。”译句：“从师学习的风尚已经很久不存在 了。”“也”为句中语气助词，起到舒缓语气的作用，没有实在意义。在翻译时，完全可以去掉。 例2：“孔子云：何陋之有？”译句：“孔子说：有什么简陋的呢？”“之”为宾语前置的标志，删去不译。 例3：“夫战，勇气也。”译句：“战斗，靠的是勇气”。“夫”为发语词，删去不译。 三.调就是调整，在翻译文言文倒装句时，应把古汉语倒装句式调整为现代汉语句式，使之符合现代汉语的表达习惯、译句通顺。这就需要调整语句语序， 大体有三种情况：

1、后置定语前移例：“群臣吏民，能面刺寡人之过者，受上赏。”可调成“能面刺寡人之过群臣吏民，受上赏。” 2、前置谓语后移例：“甚矣！汝之不惠。”可调成“汝之不惠甚矣。” 3、介宾短语前移。例：“还自扬州”可调成“自扬州还”。 4、前置宾语后移例：“何以战？”可调成“以何战？” 四.留就是保留，凡是古今意义相同的词、专有名词、国号、年号、人名、物名、人名、官职、地名等，在翻译时可保留不变。 例：“庆历四年春，滕子京谪守巴陵郡。”译句：“庆历四年的春天，滕子京被贬到巴陵郡做太守。”“庆历四年”为年号，“巴陵郡”是地名，可直接保留。 五.扩就是扩展。 1、言简义丰的句子，根据句义扩展其内容。 例：“怀敌附远，何招而不至？”译句：“使敌人降服，让远方的人归附，招抚谁，谁会不来呢？” 2、单音节词扩为同义的双音节词或多音节词。 例：“更若役，复若赋，则如何？”译句：“变更你的差役，恢复你的赋税，那么怎么样呢？”“役”“赋”扩展为双音节词。 六.缩就是凝缩，文言文中的有些句子，为了增强气势，故意实用繁笔，在翻译时应将其意思凝缩。 例：“有席卷天下，包举宇内，囊括四海之意，并吞八荒之心。”译句：“（秦）有吞并天下，统一四海的雄心。” 七.直即直译，就是指紧扣原文，按原文的词句进行对等翻译的今译方法。对于文言文的实词、大部分虚词、活用词和通假字，一般是要直接翻译的，否则， 在考查过程中是不能算作准取得翻译。 例：“清荣峻茂，良多趣味。”译句：“水清，树茂，山高，草盛，实在是趣味无穷。”

2018年牛津译林版初中英语中考英语语法全套专题练习

2018年中考英语语法专题练习 《冠词》 1.掌握不定冠词a, an的用法; 2.掌握定冠词the的用法; 3.掌握含定冠词或不定冠词的习语和固定短语; 4.掌握零冠词的用法。 ( )1. Jack is eight-year-old boy and he goes to school on foot every day. A. an; the B. a;/ C. an;/ D. a; the ( )2.一There is egg on the table. Would you like to have it? 一No, thanks. A./ B. an C. a D. the ( )3.Donald Trump, 71-year-old businessman, was chosen President of the US last year. A. a; a B. a;/ C. the; a D. the; the ( )4.Dangal (《摔跤吧!爸爸》)，Indian movie, has become one of most popular movies in China. A. a; / B. a; the C. an; the D. /;the ( )5.Every evening my daughter plays piano for an hour. A. the B. a C./ D. an ( )6.They stopped in beautiful place for camping, near farmhouse of the Smiths. A. a; a B. the; a C. a; the D. the; the ( )7.一This photo makes me think of trip to the Great Wall last year. 一Yeah, we had a great time there. A. a B. an C. the D./ ( )8.I went to supermarket to buy birthday gift for my aunt yesterday. A. an; a B. a; a C. the; / D./; the ( )9.一Do you like movie Dangal? 一Yes. It's educational movie. I like it very much. A. the; an B. a; an C. a; the D. the; a ( )10. 一Who's boy under the tree? 一Bill. He's active boy. A. a; an B. a; the C.the; a D. the; an ( )11. Shenzhen is on coast near Hong Kong. It was small village many years ago. A.a; the B.the; a C. /; / D. the; the ( )12. Lang Lang is famous pianist. He plays piano very well. A. a; the B. the; the C. the;/ D. a;/ ( )13. This is interesting story for the kids. A.an B. a C./ ( )14. I bought useful dictionary yesterday. dictionary is very cheap.

2019年高三语文一轮总复习(文言文阅读+翻译)第02课 典型例题(含解析)

2019年高三语文一轮总复习（文言文阅读+翻译）第02课典型例题 （含解析） 一、（2016年高考新课标I卷）阅读下面的文言文，完成4～7题。 曾公亮，字明仲，泉州晋江人。举进士甲科，知会稽县。民田镜湖旁，每患湖溢。公亮立斗门，泄水入曹娥江，民受其利。以端明殿学士知郑州，为政有能声盗悉窜他境至夜户不闭尝有使客亡橐中物移书诘盗公亮报吾境不藏盗殆从之者度耳索之果然公亮明练文法，更践 久，习知朝廷台阁典宪，首相 ．．，与公亮等共定大议。密 ．．韩琦每咨访焉。仁宗末年，琦请建储 州民田产银，或盗取之，大理当以强。公亮日：“此禁物也，取之虽强，与盗物民家有间矣。” 固争之，遂下有司 ．．纵人渔界河，又数通盐舟，吏不敢禁，．．议，比劫禁物法，盗得不死。契丹 皆谓：与之校，且生事。公亮言：“萌芽不禁，后将奈何？雄州赵滋勇而有谋，可任也。”使谕以指意，边害讫息。英宗即位，加中书侍郎兼礼部尚书，寻加户部尚书。帝不豫，辽使至不能见，命公亮宴于馆，使者不肯赴。公亮质之曰：“锡宴不赴，是不虔君命也。人主有疾，而必使亲临，处之安乎？”使者即就席。熙宁三年，拜司空兼侍中、河阳三城节度使。明年，起判永兴军。居一岁，还京师。旋以太傅致仕。元丰元年卒，年八十。帝临哭，辍朝三日。公亮方厚庄重，沉深周密，平居谨绳墨，蹈规矩；然性吝啬，殖货至巨万。初荐王安石，及同辅政，知上方向之，阴为子孙计，凡更张庶事，一切听顺，而外若不与之者。常遣子孝宽参其谋，至上前略无所异，于是帝益信任安石。安石德其助己，故引擢孝宽至枢密以报之。苏轼尝从容责公亮不能救正，世讥其持禄固宠云。 （节选自《宋史·曾公亮传》） 7.把文中画横线的句子翻译成现代汉语。 （1）锡宴不赴，是不虔君命也。人主有疾，而必使亲临，处之安乎? 译文：________________________________________________________________ ______________________________________________________________________ （2）苏轼尝从容责公亮不能救正，世讥其持禄固宠云。 译文：________________________________________________________________ ______________________________________________________________________ 【答案】（1）赐宴不到场，这是对君主命令的不敬。君主有病，却一定要他亲临宴会，做这样的事能心安吗？（2）苏轼曾从容地责备公亮不能纠正弊病，世人讥讽他保持禄位加固宠幸。

翻译中的归化与异化

“异化”与“归化”之间的关系并评述 1、什么是归化与异化 归化”与“异化”是翻译中常面临的两种选择。钱锺书相应地称这两种情形叫“汉化”与“欧化”。A．归化 所谓“归化”（domestication 或target-language-orientedness），是指在翻译过程中尽可能用本民族的方式去表现外来的作品；归化翻译法旨在尽量减少译文中的异国情调，为目的语读者提供一种自然流畅的译文。Venuti 认为，归化法源于这一著名翻译论说，“尽量不干扰读者，请作者向读者靠近” 归化翻译法通常包含以下几个步骤：（1）谨慎地选择适合于归化翻译的文本；（2）有意识地采取一种自然流畅的目的语文体；（3）把译文调整成目的语篇体裁；（4）插入解释性资料；（5）删去原文中的实观材料；（6）调协译文和原文中的观念与特征。 B．“异化”（foreignization或source-language-orientedness）则相反，认为既然是翻译，就得译出外国的味儿。异化是根据既定的语法规则按字面意思将和源语文化紧密相连的短语或句子译成目标语。例如，将“九牛二虎之力”译为“the strength of nine bulls and two tigers”。异化能够很好地保留和传递原文的文化内涵，使译文具有异国情调，有利于各国文化的交流。但对于不熟悉源语及其文化的读者来说，存在一定的理解困难。随着各国文化交流愈来愈紧密，原先对于目标语读者很陌生的词句也会变得越来越普遍，即异化的程度会逐步降低。 Rome was not built in a day. 归化:冰冻三尺,非一日之寒. 异化:罗马不是一天建成的. 冰冻三尺,非一日之寒 异化:Rome was not built in a day. 归化:the thick ice is not formed in a day. 2、归化异化与直译意译 归化和异化，一个要求“接近读者”，一个要求“接近作者”，具有较强的界定性；相比之下，直译和意译则比较偏重“形式”上的自由与不自由。有的文中把归化等同于意译，异化等同于直译，这样做其实不够科学。归化和异化其实是在忠实地传达原作“说了什么”的基础之上，对是否尽可能展示原作是“怎么说”，是否最大限度地再现原作在语言文化上的特有风味上采取的不同态度。两对术语相比，归化和异化更多地是有关文化的问题，即是否要保持原作洋味的问题。 3、不同层面上的归化与异化 1、句式 翻译中“归化”表现在把原文的句式（syntactical structure）按照中文的习惯句式译出。

译林版中考英语专项训练现在进行时中考真题 含答案解析

译林版中考英语专项训练现在进行时中考真题含答案解析 一、初中英语现在进行时 1．—Hurry up! —One moment. I ______ my e-mail and then I'm ready to go. A. read B. am reading C. was reading D. have read 【答案】 B 【解析】【分析】句意：——快点！——等一下。我正在看我的电子邮件，然后我就准备走了。根据答语One moment ，可知现在正在读电子邮件，要用现在进行时be（am/ is/are）+现在分词。主语I，be要用am，read的现在分词reading，故选B。 【点评】考查现在进行时的构成和用法。注意根据语境确定句子的时态。 2．It's six o'clock in the morning. Many people ______ in the park. A. are dancing B. dance C. is dancing D. dances 【答案】A 【解析】【分析】句意：现在是早上六点钟。许多人在公园里跳舞。本句指现在六点时，人们正在做的事情，句子用现在进行时态，be+动词ing。People人们，是一个复数名词，be动词用复数are。故选A. 【点评】本题考查现在进行时。 3．The writer __________his new book in the hall of our university at the moment. A. introduces B. is introducing C. introduced D. would introduce 【答案】B 【解析】【分析】句意：此刻那位作家正在我们大学的礼堂里介绍他的新书。根据时间状语at the moment可知应该用现在进行时be doing sth。故答案为B。 【点评】考查现在进行时。掌握现在进行时的意义和构成及其用法。 4．Mr Black ___ Shanghai in a few days．Do you know when the earliest plane ________ on Sunday? A. is leaving; takes off B. leaves; takes off C. is leaving; take off D. leaves; is taking off 【答案】 A 【解析】【分析】句意：布莱克先生几天后要去上海，你知道星期天最早的飞机什么时候起飞吗？根据in a few days可知句子用一般将来时，且当动词为come, go, leave时，现在进行时表示一般将来时，排除B和D。第二空中，主语是第三人称单数，动词用单三式故答案为A。 【点评】考查现在进行时和第三人称单数。掌握常用的现在进行时表将来时的动词。 5．—Eric, can you bring me the scissors? —Just a moment. I the paper-cutting with it. A. make B. made C. am making D. has made

精典文言文翻译

译文：有一天，晋平公同著名的音乐家师旷闲谈。晋平公叹了口气说：“我今年已经七十岁了，很想学习，但恐怕太晚了。” “说：“哪有身为臣子而取笑君主的呢？” 师旷连忙起身下拜，谢罪道：“臣下怎敢取笑大王？我听人家说，少年时好学，如同初升的太阳一样阳气充沛；壮年时好学，如同中午的阳光，还很强烈；老年时好学，只像蜡烛照明一样。但是，点亮蜡烛走路，与摸黑行走相比，那一个（更好）呢？” 说得好。” 秦穆公对伯乐说：“您的年纪大了，您的子孙中间有没有可以派去寻找好马的呢” 伯乐回答说：“我的子孙都是些下等之才，有个叫九方皋的人，他识别好马的本领，决不在我以下，可以告诉他识别天下最好的马的方法。请让我引见他” 秦穆公接见了九方皋，派他去寻找好马。过了三个月，九方皋回来报告说：“我已经在沙丘 找到好马了。”秦穆公问道：“是匹什么样的马呢”九方皋回答说：“是匹黄色的母马。” 秦穆公派人去把那匹马牵来，一看，却是匹纯黑色的公马。报知秦穆公，秦穆公很不高兴，把伯乐找来对他说：“您所推荐的那个找好马的人，毛色公母都不知道，又怎么能懂得什么是天下最好的马呢？”伯乐说道：“九方皋他所观察的是马的天赋的内在素质，深得它的精妙，而忘记了它的粗糙之处；明悉它的内部，而忘记了它的外表。九方皋只看见所需要看见的，看不见他所不需要看见的；只视察他所需要视察的，而遗漏了他所不需要观察的。”等到把那匹马牵回驯养使用，它果然是一匹天下难得的好马。 魏郑公（魏征）进谏劝阻唐太宗前往泰山封禅，说：“如今有一个人，患病十年，经过治疗将要痊愈。此人瘦得皮包骨头，却想要让他背着一石米，一天走上一百里路，肯定做不到。隋朝末年社会动乱，不止是十年的时间，陛下作为天下良医，百姓的疾苦虽然已经解除，但还不很富裕。要祭祀天地（向它）报告大功完成，我心里还是有疑虑。”唐太宗无言反驳。 当初，范文正公（范仲淹）被贬到饶州，朝廷正纠治朋党，士大夫都不敢前去告别，只有待制顾质独自抱病在国都城门(为范仲淹)饯行，大臣们责怪他说：“你，是长者，为什么要把自己搅进朋党里面去？”顾质说：“范先生是天下的贤人，我哪敢和他比，如果让我做了范先生的朋党，那我感到太荣幸了。”听到的人都惭愧得缩脖子。 陈寔，字仲弓，为太丘县令。一天，有一个小偷伏在屋梁上准备行窃，陈寔见到后，把自己的儿子喊过来，教训说：“不好的人，并不一定是生性如此，乃是习惯所养成的，屋梁上那一位就是这样的人。”一会儿，屋梁上的小偷跳下来，跪在地上认罪。陈寔说：“从你的外貌上看，您并不是恶人，应该是由贫困造成的。”于是，赠给他两匹布，教他一定要改正。此后，这人再没有做过小偷。 刘瞻的父亲是个贫寒的读书人，十多岁的时候，他就在郑纟因身旁管理笔墨砚台等书房用具。十八九岁的时候，郑纟因当上了御史，前往荆部商山巡视，中途在亭子里休息，俯瞰山水。当时刚刚雨过天晴，山峦秀美岩石奇丽，泉水山石分外好看。郑纟因坐了很久，起来走了五六里地，说：“如此美景，却没有作诗，就是观赏到天黑又有什么关系？”于是又返回亭子，想要往亭子上题一首诗。他忽然发现亭子上已经题了一首绝句，墨迹还没有干。郑纟因惊讶于这首诗作得出色。而当时南北方向又都没有行人。随行的人对郑纟因说：“刚才只有刘景落在后面二三里地。”郑纟因同刘景开玩笑说：“莫非是你题的吗?”刘景拜了拜说：

翻译的归化与异化

万方数据

万方数据

万方数据

万方数据

翻译的归化与异化 作者：熊启煦 作者单位：西南民族大学,四川,成都,610041 刊名： 西南民族大学学报（人文社科版） 英文刊名：JOURNAL OF SOUTHWEST UNIVERSITY FOR NATIONALITIES（HUMANITIES AND SOCIAL SCIENCE） 年，卷(期)：2005,26(8) 被引用次数：14次 参考文献(3条) 1.鲁迅且介亭杂文二集·题未定草 2.刘英凯归化--翻译的歧路 3.钱钟书林纾的翻译 引证文献(15条) 1.郭锋一小议英语翻译当中的信达雅[期刊论文]-青春岁月 2011(4) 2.许丽红论汉英语言中的文化差异与翻译策略[期刊论文]-考试周刊 2010(7) 3.王笑东浅谈汉英语言中的差异与翻译方法[期刊论文]-中国校外教育（理论） 2010(6) 4.王宁中西语言中的文化差异与翻译[期刊论文]-中国科技纵横 2010(12) 5.鲍勤.陈利平英语隐喻类型及翻译策略[期刊论文]-云南农业大学学报(社会科学版) 2010(2) 6.罗琴.宋海林浅谈汉英语言中的文化差异及翻译策略[期刊论文]-内江师范学院学报 2010(z2) 7.白蓝跨文化视野下文学作品的英译策略[期刊论文]-湖南社会科学 2009(5) 8.王梦颖探析汉英语言中的文化差异与翻译策略[期刊论文]-中国校外教育（理论） 2009(8) 9.常晖英汉成语跨文化翻译策略[期刊论文]-河北理工大学学报（社会科学版） 2009(1) 10.常晖对翻译文化建构的几点思考[期刊论文]-牡丹江师范学院学报（哲学社会科学版） 2009(4) 11.常晖认知——功能视角下隐喻的汉译策略[期刊论文]-外语与外语教学 2008(11) 12.赵勇刚汉英语言中的文化差异与翻译策略[期刊论文]-时代文学 2008(6) 13.常晖.胡渝镛从文化角度看文学作品的翻译[期刊论文]-重庆工学院学报(社会科学版) 2008(7) 14.曾凤英从文化认知的视角谈英语隐喻的翻译[期刊论文]-各界 2007(6) 15.罗琴.宋海林浅谈汉英语言中的文化差异及翻译策略[期刊论文]-内江师范学院学报 2010(z2) 本文链接：https://www.doczj.com/doc/6a1926994.html,/Periodical_xnmzxyxb-zxshkxb200508090.aspx

译林版中考英语专项训练冠词专项复习

译林版中考英语专项训练冠词专项复习 一、初中英语冠词 1．I'm going to have picnic on Sunday. A. the; an B. an; the C. a; / D. an; / 【答案】 C 【解析】【分析】句意：星期天我要去野餐。固定短语，have a picnic，野炊；on Sunday，在周日。故选C。 【点评】考查冠词的基本用法。注意熟记固定搭配。 2．I spend_______ hour playing _________drums everyday. A. a；the B. an；/ C. an；the 【答案】 C 【解析】【分析】句意：我每天花费一个小时打鼓。本题考查冠词。a用在辅音音素开头的可数名词单数前，an用在元音音素开头的可数名词单数前；hour的第一个音素是元音音素 /a?/，故排除选项A；又因为乐器前使用冠词the；故答案为C。 【点评】考查冠词的用法，弄清a与an的差异。 3．—My daughter seldom has breakfast. —It's ________unhealthy habit. Breakfast is very important to health. A. a B. an C. the 【答案】B 【解析】【分析】句意：—我女儿很少吃早饭。—那是一个不健康的习惯，早饭对健康非常重要。根据句意可知是表示数量一，用不定冠词a/an，一个。a用于辅音音素开头的单词前，an用于元音音素开头的单词前；unhealthy是元音音素开头的单词，故选B。 【点评】考查冠词辨析，注意不定冠词和定冠词的词义和用法。 4．_______moon is very bright at night. A. A B. An C. The D. / 【答案】C 【解析】【分析】句意：月亮在晚上很明亮。moon表示独一无二的事物，所以前用定冠词the，故答案为C。 【点评】考查冠词的用法，在表示独一无二的名词前用the。 5．—What do you usually have for breakfast？ —Some bread，________ egg and a glass of milk． A. a B. an C. the D. / 【答案】 B 【解析】【分析】考查不定冠词．句意：﹣﹣你早餐通常吃什么？﹣﹣一些面包．一个鸡

高考文言文翻译十年试题例析(一)

高考文言文翻译难点实词十年试题总结（一）你在读书上花的任何时间，都会在某一个时刻给你回报。——董卿《中国诗词大会》 你在学习上花的任何努力，都会在高考时刻给你回报。----寄同学们 声明：部分内容来源网络，版权归原作者。 1【谙】①熟悉，知晓。例1、江南好，风景旧曾谙。例2、二人久居江东，谙习水性。（《三国演义·群英会蒋干中计》）②熟记，记诵。虽复一览便谙。（《南齐书·陆澄传》）2【按】①查看，察看。按西域书，阿罗汉诺矩罗居震旦东南大海际雁荡山……（《雁荡山》） ②审查，核查。例1、以吴民之乱请于朝，按诛五人。（《五人墓碑记》） 例2、安到郡，不入府，先往按狱，理其无明验者，条上出之。（《后汉书·袁张韩周列传》袁安到郡后，不进官府，先去审查案件，查出那些没有明确证据的犯人，上奏要求放他们出狱。） ③巡查，巡行。例1、部使者臧，新贵，将按郡至袁。（2007福建卷，高启《书博鸡者事》江西湖东道肃政廉访司有一个姓臧的，新近做了高官，将要巡查所管各州郡，来到袁地。）例2、曩胡公按部，令所过毋供张。（《明史·海瑞转》刚才胡公巡查所部地区，命令经过的地区不要办礼物准备招待。） ④压抑，止住。按助强弱。⑤于是，就。 3【案】①通“按”，察看，查看。召有司案图，指从此以往十五都予赵。（《廉颇蔺相如列传》） ②通“按”，考察，核实。案贤圣之言，上下多相违（互相矛盾）。 ③通“按”，巡行，巡查。宣王案行其营垒，曰：“天下奇才也。” ④通“按”，用手压或按。例1、案灌夫项令谢（道歉）。 例2、（高进之）案腰间刀伺道济，有异言，则杀之。道济趋下阶，叩头曰：“武皇帝在上，臣道济如有异心，速殛之。”（2007广东卷，高进之此时用手按住腰间的刀窥探檀道济，如果他有异言，就杀掉他。檀道济快步走下台阶，叩头说：“武皇帝在上，我檀道济如有异心，就赶快诛杀我。”） ⑤文书，案卷。无丝竹之乱耳，无案牍之劳形。 4【暗】①愚昧，糊涂。例1、水府幽深，寡人暗昧，夫子不远千里，将有为乎？（《柳毅传》） 例2、刘璋暗弱。（《三国志·隆中对》，昏庸无能，胆小懦弱。）例3、兼听则明，偏信则暗。 ②悄悄地，默默地。寻声暗问弹者谁？（《琵琶行》）群书万卷常暗诵。（杜甫《可叹》） ③私下里，不公开的；隐蔽地，隐藏不露的。例1、明察暗访例2、龙门水尤湍急，多暗石。 5【媪】①对老年妇女的尊称。老臣以媪为长安君计短也。（《触龙说赵太后》）②泛指妇女。其父郑季，为吏，给事平阳侯家，与侯妾卫媪通，生青。（《史记·卫将军骠骑列传》） B 6【拔】①攻取，攻下。例1、其后秦伐赵，拔石城。（《廉颇蔺相如列传》）例2、汉乃进军攻广都，拔之。（2008江苏卷，吴汉挥师直攻广都，迅速攻克。） ②突出，超出。例1、天姥连天向天横，势拔五岳掩赤城。出类拔萃。例2、吾读严子祺先之文，深叹其能矫然拔俗也。（2011湖南卷,） ③提拔。山涛作冀州（的长官），甄（审查）拔三十余人。 7【罢】①停止，结束。例1、于是罢酒，侯生遂为上客。（《史记·信陵君窃符救赵》）例 2、曲罢曾教善才服，妆成每被秋娘妒。例 3、语罢暮天钟。 ②散，散集。罢市。