The replicative success of vaccinia virus (VACV) depends on its ability to subvert host functions. Poxviruses multiplication and maturation are closely associated with the endoplasmic reticulum (ER) and its membranes. This organelle responds to disturbances caused by the accumulation of misfolded proteins, leading to processing of these proteins or even programmed cell death through the unfolded protein response (UPR). Several studies show that different viruses can activate UPR pathway components and negatively modulate others. Here, we investigate the effects of infections by zoonotic VACV strains from Brazil, Guarani P1 virus (GP1V) and Passatempo virus (PSTV), in the activation of UPR pathway sensors. We observed translocation of ATF6 to the nucleus as well as transcriptional increase after GP1V, PSTV, and reference strain Western Reserve (WR) infection. XBP1 processing appears to be negatively modulated after VACV infection; however, inhibition of the inositol-requiring enzyme 1 (IRE1) kinase domain led to a reduction in plaque sizes for these viruses. The absence of PKR-like endoplasmic reticulum kinase (PERK) has an impact on the plaque phenotype of GP1V, PSTV viruses, as well as for the prototypical strain WR. These results indicate that the VACV manipulates the three arms of the UPR path differently to ensure replicative success.
XuCBailly-MaitreBReedJC.Endoplasmic reticulum stress: cell life and death decisions.J Clin Invest2005;115:2656–64
2.
HussainSGRamaiahKV.Endoplasmic reticulum: stress, signalling and apoptosis.Curr Sci2007;93:1684–96
3.
MarciniakSJRonD.Endoplasmic reticulum stress signaling in disease.Physiol Rev2006;86:1133–49
4.
LiJNiMLeeBBarronEHintonDRLeeAS.The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells.Cell Death Differ2008;15:1460–71
5.
TolonenNDoglioLSchleichSKrijnse LockerJ.Vaccinia virus DNA replication occurs in endoplasmic reticulum-enclosed cytoplasmic mini-nuclei.Mol Biol Cell2001;12:2031–46
6.
Da FonsecaFGKroonEGNogueiraMLde Souza TrindadeG.Zoonotic vaccinia virus outbreaks in Brazil.Future Virology2011;6:697–707
7.
LeãoTLda FonsecaFG.Subversion of cellular stress responses by poxviruses.World J Clin Infect Dis2014;4:27–40
8.
LeiteJADrumondBPTrindadeGSLobatoZIda FonsecaFGdosSJMadureiraMCGuedesMIFerreiraJMBonjardimCAFerreiraPCKroonEG.Passatempo virus, a vaccinia virus strain, Brazil.Emerg Infect Dis2005;11:1935–41
9.
TrindadeGSLobatoZIDrumondBPLeiteJATrigueiroRCGuedesMIda FonsecaFGdos SantosJRBonjardimCAFerreiraPCKroonEG.Isolation of two vaccinia virus strains from a single bovine vaccinia outbreak in rural area from Brazil: implications on the emergence of zoonotic orthopoxviruses.Am J Trop Med Hyg2006;75:486–90
10.
CamposMKroonEG.Critical period for irreversible block of vaccinia virus-replication.Rev Microbiol1993;24:104–10
11.
JoklikWK.The purification of four strains of poxvirus.Virology1962;18:9–18
12.
WangYChaudhriGJacksonRJKarupiahG.IL-12p40 and IL-18 play pivotal roles in orchestrating the cell-mediated immune response to a poxvirus infection.J Immunol2009;183:3324–31
13.
NadanakaSYoshidaHKanoFMurataMMoriK.Activation of mammalian unfolded protein response is compatible with the quality control system operating in the endoplasmic reticulum.Mol Biol Cell2004;15:2537–48
14.
VandesompeleJDe PreterKPattynFPoppeBVan RoyNDe PaepeASpelemanF.Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.Gen Biol2002;3:1–12
SmithGLMcFaddenG.Smallpox: anything to declare.Nat Rev Immunol2002;2:521–7
17.
JohnstonJBMcFaddenG.Poxvirus immunomodulatory strategies: current perspectives.J Virol2003;77:6093–100
18.
SeetBTJohnstonJBBrunettiCRBarrettJWEverettHCameronCSypulaJNazarianSHLucasAMcFaddenG.Poxviruses and immune evasion.Annu Rev Immunol2003;21:377–423
19.
LourençoKLChináliaLAHenriquesLRRodriguesRALda FonsecaFG.Zoonotic vaccinia viruses belonging to different genetic clades exhibit immunomodulation abilities that are proportional to their pathogenic potential.Virol J2021;18:124
20.
Galindo BarrealesIHernáezBMuñoz-MorenoRCuesta-GeijoMADalmau-MenaIAlonsoC.The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection.Cell Death Dis2012;3:e341
21.
AmbroseRLMackenzieJM.ATF6 signaling is required for efficient West Nile virus replication by promoting cell survival and inhibition of innate immune responses.J Virol2013;87:2206–14
22.
SongJChiMLuoXSongQXiaDShiBHanJ.Non-structural protein 2B of human rhinovirus 16 activates both PERK and ATF6 rather than IRE1 to trigger ER stress.Viruses2019;11:133
23.
BlascoRMossB.Role of cell-associated enveloped vaccinia virus in cell-to-cell spread.J Virol1992;66:4170–9
24.
LeãoTLLourençoKLDe Oliveira QueirozCSerufoAVMendes da SilvaABarbosa-StancioliEFGuimarães da FonsecaF.Vaccinia virus induces endoplasmic reticulum stress and activates unfolded protein responses through the ATF6α transcription factor.Virol J2023;20:145. DOI:10.1186/s12985-023-02122-y.
25.
TardifKDMoriKKaufmanRJSiddiquiA.Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response.J Biol Chem2004;279:17158–64
26.
PasqualGBurriDJPasquatoAde la TorreJCKunzS.Role of the host cell’s unfolded protein response in arenavirus infection.J Virol2011;85:1662–70
27.
SungSCChaoCYJengKSYangJYLaiMM.The 8ab protein of SARS-CoV is a luminal ER membrane-associated protein and induces the activation of ATF6.Virology2009;387:402–13
28.
Echavarría-ConsuegraLCookGMBusnadiegoILefèvreCKeepSBrownKDoyleNDowgierGFranaszekKMooreNASiddellSGBickertonEHaleBGFirthAEBrierleyIIrigoyenN.Manipulation of the unfolded protein response: a pharmacological strategy against coronavirus infection.PLoS Pathog2021;17:e1009644
29.
AoeT.Pathological aspects of COVID-19 as a conformational disease and the use of pharmacological chaperones as a potential therapeutic strategy.Front Pharmacol2020;11:1095
30.
SuredaAAlizadehJNabaviSFBerindan-NeagoeICismaruCAJeandetPŁosMJClementiENabaviSMGhavamiS.Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?Eur J Pharmacol2020;882:173288
31.
IslerJASkaletAHAlwineJC.Human cytomegalovirus infection activates and regulates the unfolded protein response.J Virol2005;79:6890–9
32.
SuAWangHLiYWangXChenDWuZ.Opposite roles of RNase and kinase activities of inositol-requiring enzyme 1 (IRE1) on HSV-1 replication.Viruses2017;9:235
33.
MartinonFChenXLeeAHGlimcherLH.Toll-like receptor activation of XBP1 regulates innate immune responses in macrophages.Nat Immunol2010;11:411
34.
Silva GomesJAde AraújoFFde Souza TrindadeGQuinanBRDrumondBPFerreiraJMMotaBENogueiraMLKroonEGSantos AbrahãoJCôrrea-OliveiraRda FonsecaFG.Immune modulation in primary vaccinia virus zoonotic human infections.Clin Dev Immunol2012;2012:974067
35.
XueMFuFMaYZhangXLiLFengLLiuP.The PERK arm of the unfolded protein response negatively regulates transmissible gastroenteritis virus replication by suppressing protein translation and promoting type I interferon production.J Virol2018;92:e00431–e10018
36.
SoodRPorterACMaKQuilliamLAWEKRC.Pancreatic eukaryotic initiation factor-2α kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress.Biochem J2000;346:281–93
37.
LanglandJOJacobsBL.The role of the PKR-inhibitory genes, E3L and K3L, in determining vaccinia virus host range.Virology2002;299:133–41
38.
LyooHRParkSYKimJYJeongYS.Constant up-regulation of BiP/GRP78 expression prevents virus-induced apoptosis in BHK-21 cells with Japanese encephalitis virus persistent infection.Virol J2015;12:18
