LitCovid-sentences  

PMC:7281546 / 19950-51014 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T143 0-2 Sentence denotes 4.
T144 3-40 Sentence denotes Innate Immunity during PEDV Infection
T145 41-277 Sentence denotes Host cells generally defend against virus infection by mounting an innate antiviral immune response to prevent the spread of the infection and aid in initiating an adaptive immune response which eventually removes the viruses from host.
T146 278-495 Sentence denotes Therefore, the first barrier to restrain viral infections is the host innate immune system, which is related to multiple proteins and mechanisms, including IFNs, inflammatory cytokine, apoptosis, autophagy, and so on.
T147 497-501 Sentence denotes 4.1.
T148 502-527 Sentence denotes Overview of IFN Responses
T149 528-860 Sentence denotes The activation of type I IFN responses is composed of three stages: (1) recognition of pathogen-associated molecular pattern (PAMP) by PRRs; (2) secretion of type I IFNs through paracrine or autocrine pathways; and (3) expression of numerous antiviral IFN-stimulated genes (ISGs) which bring the host into the antiviral state [136].
T150 861-1339 Sentence denotes At least three important PRRs have been identified in recognition of viral nucleic acids, including retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) (detection of viral RNA in the cytoplasm) [137], the membrane-bound Toll-like receptors (TLRs) (recognition of viral RNA or DNA in the endosome) [138], as well as a structurally unrelated group of viral DNA sensors (e.g., cGAS (cyclic GMP-AMP synthase) and IFI16) localized in the host cytoplasm and/or nucleus [139].
T151 1340-1472 Sentence denotes In the cytosol, the formation of specific secondary structure of viral RNA is closely related to viral RNA delivery and replication.
T152 1473-1672 Sentence denotes These molecular signatures are detected by RLRs including RIG-I (also known as DDX58), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology-2 (LGP2) [140,141].
T153 1673-1870 Sentence denotes PRRs recognize PAMPs, inducing an intracellular signaling cascade, thus leading to the activation of transcription factors such as IRFs and NF-κB, which in turn induce the production of IFNs [142].
T154 1871-2047 Sentence denotes Both RIG-I and MDA5 have two N-terminal CARD domains to interact with the CARD domains of the downstream adaptor proteins, and a DEAD/H-box RNA helicase domain for RNA binding.
T155 2048-2337 Sentence denotes However, LGP2 does not have the N-terminalCARD domains, and the involved functions remain unclear [143,144,145]. dsRNA, as a specific secondary structure of viral RNA, can be sensed by RIG-I/MDA5 to induce IFN-α/β production through the cascade activation of the RLR pathway [146,147,148].
T156 2338-2535 Sentence denotes Activated RIG-I/MDA5 forms homo-oligomers and recruits the adaptor mitochondrial antiviral signaling (MAVS) to induce the formation of signaling complex of MAVS with other proteins on mitochondria.
T157 2536-2751 Sentence denotes TNF receptor-associated factor 6 (TRAF6) associates with TNFR1-associated death domain protein (TRADD), tripartite motif 14 (TRIM14), and pyruvate carboxylase (PC), resulting in the activation of IκB kinases (IKKs).
T158 2752-2884 Sentence denotes IKKs (IKKα, IKKβ and IKKγ) phosphorylate NF-κB inhibitor (IκB), leading to the ubiquitination of IκB and its subsequent degradation.
T159 2885-3003 Sentence denotes NF-κB is then activated and translocated into the nucleus to turn on the expression of proinflammatory and type I IFN.
T160 3004-3197 Sentence denotes MAVS also recruits and activates TBK1/IKKε by TRAFs that are pre-associated with TBK1/IKKε, via direct interaction between the SDD domain of TBK1/IKKε and the coiled-coil domain of TRAFs [149].
T161 3198-3352 Sentence denotes Activated TBK1/IKKε phosphorylates IFN regulatory factors (IRF3/IRF7), that further dimerize and import into the nucleus to promote type I IFN production.
T162 3353-3496 Sentence denotes On the other hand, MAVS interacts with MITA (also known as STING), that is located in mitochondria and the endoplasmic reticulum (ER) membrane.
T163 3497-3607 Sentence denotes MITA interacts with the TRAP complex, which may be involved in recruiting TBK1 and IKKε to phosphorylate IRF3.
T164 3608-3708 Sentence denotes Ubiquitination and deubiquitination are decisive in the regulation of RLR pathways activation [150].
T165 3709-3845 Sentence denotes Upon binding to viral dsRNA, RIG-I and MDA5 undergo conformational changes and release the N-terminal tandem CARD domains [151,152,153].
T166 3846-3982 Sentence denotes The CARD domains of RIG-I are modified by lysine 63 (K63) polyubiquitin chains through the ubiquitin ligases TRIM25, RNF135, and RIPLET.
T167 3983-4048 Sentence denotes This modification is crucial for RIG-I to recruit MAVS [154,155].
T168 4049-4252 Sentence denotes In addition to the ubiquitination of RLRs, the polyubiquitylation of TRAF3 and TRAF6 also play an important role in the regulation of innate immune signaling by activation of TBK1 and IKKs, respectively.
T169 4253-4423 Sentence denotes The K63 polyubiquitin chains can be removed by DUBs such as the tumor suppressor protein CYLD, DUBA and A20, providing a mechanism to downregulate immune responses [156].
T170 4424-4520 Sentence denotes Ubiquitination and deubiquitination are in a dynamic equilibrium to maintain immune homeostasis.
T171 4521-4640 Sentence denotes Type I IFNs are secreted by secretory cells and peripheral cells through self-secretion or paracrine secretion manners.
T172 4641-4879 Sentence denotes Extracellular type I IFNs bind to a heterodimeric complex composed of subunits of IFN-α receptors 1 (IFNAR1) and 2 (IFNAR2) located on the cell surface, which activates the tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) signal transducer.
T173 4880-5092 Sentence denotes TYK2/JAK1 subsequently induces the phosphorylation of transcription factors STAT1 and STAT2, which dimerize and in turn recruit IFN-regulatory factor 9 (IRF9), to form STAT1-STAT2-IRF9 trimerized complex (ISGF3).
T174 5093-5248 Sentence denotes This complex then translocates to the nucleus, where it binds to the IFN-stimulated response elements (ISRE motif; conserved sequence is TTTCNNTTTC) [157].
T175 5249-5409 Sentence denotes The binding of ISGF3 to ISRE finally triggers expression of IFN-stimulated genes (ISGs) that directly or indirectly exert antiviral effects in host cells [157].
T176 5410-5473 Sentence denotes Three types of IFNs (types I, II and III) have been identified.
T177 5474-5524 Sentence denotes Type I and type II IFNs have been widely reported.
T178 5525-5557 Sentence denotes Type II IFNs only contain IFN-γ.
T179 5558-5717 Sentence denotes IFN-γ is produced by natural killer (NK) cells and activated CD4+ and CD8+ T cells in response to the cytokines such as interleukin-12 (IL-12) and IL-18 [158].
T180 5718-5802 Sentence denotes IFN-γ binds to the type II IFN receptor composed of two subunits, IFNGR1 and IFNGR2.
T181 5803-5868 Sentence denotes IFNGR1 and IFNGR2 induce the formation of STAT1-STAT1 homodimers.
T182 5869-6050 Sentence denotes STAT1-STAT1 homodimers translocate to the nucleus and bind to the promoter of the IFN-γ-activation site (GAS) elements, to initiate the transcription of IFN-γ-regulated genes [159].
T183 6051-6183 Sentence denotes Type III IFNs have been explored in recent years, to unravel the underlying mechanisms that manipulate host innate immune responses.
T184 6184-6309 Sentence denotes Type III IFNs in humans contains IFN-λ1 (interleukin 29 [IL-29]), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B), and IFN-λ4 [160,161,162].
T185 6310-6416 Sentence denotes Their expression profiles, signaling pathways, and gene expression programs resemble those of type I IFNs.
T186 6417-6569 Sentence denotes The production of type I and III IFNs are both initiated through the recognition of PAMPs or damage associated molecular patterns (DAMPs) by PRRs [163].
T187 6570-6814 Sentence denotes Despite the fact that the same transcriptional factors are required for the activation of promoters of type I and III IFNs, the NF-κB pathway is a pivotal regulator in IFN-λ production, whereas the IRFs pathway dominates type I IFNs expression.
T188 6815-6914 Sentence denotes The promoter of IFN-λ1 includes more NF-κB binding sites compared with in the IFN-β promoter [164].
T189 6915-7038 Sentence denotes The signal transduction of type III IFNs depends on the IFN-λ-specific receptor, IL-28Ra chain and IL-10R2 chain [161,165].
T190 7039-7269 Sentence denotes Synthetic IFN-λ binds to IL-28Rα and induces a conformational change within the receptor subunits, that triggers the activation of the receptor-associated tyrosine kinases (TYK2 and JAK1), which then phosphorylate STAT1 and STAT2.
T191 7270-7494 Sentence denotes STAT1 and STAT2 are heterodimerized and interact with IRF9 to form the ISGF3 transcription complex that binds to ISRE in the promoters of ISGs, to induce the expression of hundreds of proteins with antiviral functions [166].
T192 7496-7500 Sentence denotes 4.2.
T193 7501-7534 Sentence denotes Immune Evasion Mechanisms of PEDV
T194 7535-7654 Sentence denotes Induction of IFN-α/β is the most rapid and effective mechanism for hosts to initiate antiviral innate immune responses.
T195 7655-7711 Sentence denotes SARS-CoV, MHV and many other CoVs are sensitive to IFNs.
T196 7712-7868 Sentence denotes A great number of viral dsRNAs intermediates are generated during CoVs infection that contribute to IFN production, but these CoVs remain highly pathogenic.
T197 7869-8035 Sentence denotes As a matter of fact, CoVs have developed a set of elaborate mechanisms to evade or inhibit the host antiviral innate immune response during virus evolution [134,167].
T198 8036-8396 Sentence denotes The evasive strategies utilized by PEDV are classified into four major types: (1) inhibition of RLRs-mediated IFN production pathways, (2) inhibition of the activation of transcription factors responsible for IFN induction, (3) disruption of the signal cascades induced by IFN, and (4) hiding its viral RNA to avoid the exposure of viral RNA to immune sensors.
T199 8397-8588 Sentence denotes In the past decade, accumulating evidence demonstrates that PEDV N protein, nsp1, PLP2, nsp5, nsp15, and nsp16 antagonize type I IFN or type III IFNs production [58,65,78,80,100,132,135,168].
T200 8589-8694 Sentence denotes This explains why only weak IFNs’ and cytokines’ expression is detected in PEDV-infected cells [169,170].
T201 8696-8702 Sentence denotes 4.2.1.
T202 8703-8717 Sentence denotes PEDV N Protein
T203 8718-8891 Sentence denotes N protein, as an abundantly produced structural protein within CoV-infected cells, has multiple functions, including virus replication, transcription, and assembly [56,134].
T204 8892-9046 Sentence denotes PEDV N protein has been identified as an IFN antagonist that blocks the expression of IFN-β and ISGs by suppression of the IRF3 and NF-κB activities [58].
T205 9047-9244 Sentence denotes PEDV N protein inhibits the activation of the IFN-β promoter induced by TBK1 and its upstream RIG-I, MDA-5, VISA, and TRAF3, while not affecting the activation of the IFN-β promoter driven by IRF3.
T206 9245-9435 Sentence denotes Further experiments confirm that N directly interacts with TBK1 to obstruct the association between TBK1 and IRF3, which inhibits TBK1-induced IRF3 phosphorylation and IFN-β production [58].
T207 9436-9532 Sentence denotes Moreover, the effect of PEDV N protein on type III IFN production has also been evaluated [168].
T208 9533-9775 Sentence denotes N protein inhibits polyinosinic-polycytidylic acid (poly(I:C))-induced IFN-λ3 production by blocking the nuclear translocation of NF-κB, but does not antagonize the type I or type II IFN expression induced by poly(I:C) in IPEC-J2 cells [168].
T209 9776-9914 Sentence denotes Recent studies show that SARS-CoV N protein inhibits type I IFN production through suppressing TRIM25-mediated RIG-I ubiquitination [171].
T210 9915-9998 Sentence denotes The MERS-CoV N protein also blocks IFN production by interacting with TRIM25 [171].
T211 9999-10231 Sentence denotes In addition, both MHV and SARS-CoV N proteins perturb the function of cellular protein activator of protein kinase R (PACT), which can bind to RIG-I and MDA5 to activate IFN production, and thus antagonize type-I IFN signaling [61].
T212 10232-10342 Sentence denotes These results indicate the important function of the CoVs N protein in modulating host innate immune response.
T213 10343-10412 Sentence denotes Whether PEDV N protein targets TRIM25 or PACT should be investigated.
T214 10413-10623 Sentence denotes Although several studies have been performed to understand the pathogenicity of PEDV, there remains limited information about the interaction between viral proteins and host cell factors during viral infection.
T215 10624-10693 Sentence denotes CoV N protein is a vital viral protein involved in virus replication.
T216 10694-10889 Sentence denotes Current researches have indicated that N protein interacts with many host proteins, such as hCypA [172], proteasome subunit p42 [173], Smad3 [174], hnRNP-A1 [175], and the chemokine CXCL16 [176].
T217 10890-10966 Sentence denotes In the host cells, a large number of host proteins reveal various functions.
T218 10967-11046 Sentence denotes However, for the virus, the genome only encodes several limited viral proteins.
T219 11047-11159 Sentence denotes Therefore, these viral proteins have to be multifunctional, which is pivotal to virus replication and existence.
T220 11161-11167 Sentence denotes 4.2.2.
T221 11168-11177 Sentence denotes PEDV nsp1
T222 11178-11338 Sentence denotes PEDV nsp1 is the N-terminal cleavage product from polyproteins pp1a and pp1a/b processed by nsp3 and nsp5 [177] and is about 110 amino acids in length [74,178].
T223 11339-11486 Sentence denotes Nsp1 of many α-CoV and β-CoV exhibits both functional conservation and mechanistic diversity in suppressing host gene expression and IFN signaling.
T224 11487-11646 Sentence denotes For SARS-CoV, nsp1 triggers the decay and cleavage of host mRNA and inhibits host protein translation, subsequently inhibiting type I IFN production [179,180].
T225 11647-11784 Sentence denotes SARS-CoV nsp1 also blocks the expression of IFN-inducible genes, by restraining the signal transduction during virus infection [181,182].
T226 11785-11875 Sentence denotes The TGEV nsp1 considerably suppresses host protein expression during viral infection [77].
T227 11876-12001 Sentence denotes Structural studies show that the core structure of PEDV nsp1 is highly similar to those of SARS-CoV nsp1 and TGEV nsp1 [183].
T228 12002-12230 Sentence denotes PEDV nsp1 inhibits host gene expression and three motifs (amino acids 67 to 71, 78 to 85, and 103 to 110) form a stable functional region for inhibition of host protein synthesis, differing considerably from SARS-CoV nsp1 [183].
T229 12231-12348 Sentence denotes PEDV nsp1 has been identified as an IFN antagonist, which constrains poly (I:C)-induced IFN-β promoter activity [65].
T230 12349-12508 Sentence denotes Nsp1 significantly inhibits the activation of IFN-β promoter triggered by IRF3, whereas it does not inhibit IRF3 phosphorylation and its nuclear translocation.
T231 12509-12663 Sentence denotes Nsp1 interrupts the association of IRF3 with CREB-binding protein (CBP), by promoting CBP degradation in the nucleus via the proteasome-dependent pathway.
T232 12664-12804 Sentence denotes CBP/p300, the transcription co-activator cAMP responsive element binding protein (CREB), forms a complex with the activated IRF3 in nucleus.
T233 12805-13044 Sentence denotes The IRF3-CBP/p300 complex binds to the positive regulatory domain (PRD) regions of the IFN-β promoter, to assemble the enhanceosome with NF-κB and other factors, which ultimately turn on the transcription of type I IFN genes [184,185,186].
T234 13045-13110 Sentence denotes Therefore, PEDV nsp1 blocks type I IFN production in the nucleus.
T235 13111-13243 Sentence denotes Activated NF-κB induces the production of type I IFNs and proinflammatory cytokines and is important for inhibiting viral infection.
T236 13244-13393 Sentence denotes PEDV nsp1 has been shown to interfere with the NF-κB activity [78] and is the most potent suppressor of proinflammatory cytokines at early infection.
T237 13394-13588 Sentence denotes It inhibits the phosphorylation and degradation of IκBα, and blocks p65 nuclear translocation, leading to the suppression of both IFN and the early production of pro-inflammatory cytokines [78].
T238 13589-13747 Sentence denotes Moreover, PEDV inhibits type III IFN production and nsp1, nsp3, nsp5, nsp8, nsp14, nsp15, nsp16, ORF3, E, M, and N are identified as type III IFN antagonists.
T239 13748-13814 Sentence denotes Among these antagonists, nsp1 is the most potent suppressor [130].
T240 13815-13955 Sentence denotes PEDV nsp1 blocks the nuclear translocation of IRF1 and decreases the amounts of peroxisomes and then suppresses IRF1-mediated type III IFNs.
T241 13956-14038 Sentence denotes The conserved residues of PEDV nsp1 protein are crucial for IFN suppression [130].
T242 14039-14184 Sentence denotes Multiple effects of nsp1 on modulating innate immune response during PEDV infection suggest the vital role of nsp1 in the PEDV replication cycle.
T243 14186-14192 Sentence denotes 4.2.3.
T244 14193-14197 Sentence denotes PLP2
T245 14198-14556 Sentence denotes The antiviral innate immune signaling pathways are regulated by several posttranslational modifications (PTMs), such as phosphorylation, ubiquitination, glycosylation, NEDDylation and SUMOylation [187], of which ubiquitination is a critical modification to modulate the stability and activity of PRRs and other components of innate immune signaling pathways.
T246 14557-14712 Sentence denotes During viral infection, a reciprocatory action (occurrence of ubiquitination and deubiquitination) helps maintain the homeostasis of host immune responses.
T247 14713-14823 Sentence denotes Hence, deubiquitinases (DUBs) are indispensable in the regulation of virus-induced type I IFN signaling [188].
T248 14824-14935 Sentence denotes Many host DUBs have been reported engaging in the regulation of innate immune signaling pathways [189,190,191].
T249 14936-15081 Sentence denotes In recent years, a variety of viral DUBs have been discovered to target key components of type I IFN pathway during various RNA virus infections.
T250 15082-15325 Sentence denotes For example, foot-and-mouth disease virus leader proteinase (FMDV Lbpro) [192], and porcine reproductive and respiratory syndrome virus nsp2 (PRRSV nsp2) possess ubiquitin-deconjugating activity to deubiquitinate key host components [193,194].
T251 15326-15438 Sentence denotes To counteract host antiviral response, CoVs likely take advantage of DUB activity to break host innate immunity.
T252 15439-15586 Sentence denotes Indeed, the PLPs of mouse hepatitis virus A59 (MHV-A59) [195], SARS [196], and human CoV NL63 have DUB activity and antagonize IFN induction [197].
T253 15587-15715 Sentence denotes PEDV PLP2 has been reported as having a deubiquitinase activity as well, and it can be co-immunoprecipitated by RIG-I and STING.
T254 15716-15885 Sentence denotes As mentioned above, FMDV Lbpro, MHV PLP2 and SARS PLPs all counteract host innate immune response through blocking the ubiquitination of the components of RLRs pathways.
T255 15886-16031 Sentence denotes Similarly, PEDV PLP2 removes the ubiquitinated conjugates from RIG-I and STING by its DUB activity, to negatively regulate type I IFN production.
T256 16032-16195 Sentence denotes PEDV PLP2 probably interacts with RIG-I and STING, which prevents the activation of RIG-I and STING by hindering the recruitment of downstream signaling molecules.
T257 16196-16316 Sentence denotes As expected, the interference with the ubiquitination of RIG-I and STING by PLP2 clearly benefits PEDV replication [80].
T258 16317-16377 Sentence denotes PEDV nsp3 contains two core domains of PLPs (PLPl and PLP2).
T259 16378-16481 Sentence denotes It is determined that PEDV PLP2, but not PLP1, inhibits the IFN-β promoter activation in HEK293T cells.
T260 16482-16553 Sentence denotes The DUB activity of PLP2 is highly dependent on its catalytic activity.
T261 16554-16735 Sentence denotes Three catalytically inactive mutants of PEDV PLP2 (C1729A, H1888A and D1901A) are defective in the deubiquitination of its targets and fail to impair virus-induced IFN-β production.
T262 16736-16916 Sentence denotes SARS-CoV PLP2 interacts with MDM2 (mouse double minute 2 homolog) to deubiquitinate and stabilize MDM2, approving the degradation of p53 and the suppression of IFN signaling [198].
T263 16917-16986 Sentence denotes PEDV infection degrades p53 by upregulation of MDM2 expression [198].
T264 16987-17112 Sentence denotes PEDV PLP2 may be responsible for targeting the p53 pathway and inhibiting p53-dependent apoptosis, leading to immune evasion.
T265 17113-17286 Sentence denotes A recent study determined that TGEV PL1 inhibits the IFN-β expression and interferes with the RIG-1- and STING-mediated signaling pathway through a viral DUB activity [195].
T266 17287-17402 Sentence denotes It suggests that different viral proteins are involved in the deubiquitination of host proteins for different CoVs.
T267 17403-17557 Sentence denotes However, these studies offer a probability to design a common therapeutic against different viral DUBs to reduce the replication and pathogenesis of CoVs.
T268 17558-17732 Sentence denotes Therefore, further studies are required to understand more about the substrate specificity of these viral DUBs and clarify the precise functions of CoV protease/DUB activity.
T269 17734-17740 Sentence denotes 4.2.4.
T270 17741-17750 Sentence denotes PEDV nsp5
T271 17751-17858 Sentence denotes Notably, 3Cpro is a critical IFN antagonistic protein identified in multiple different families of viruses.
T272 17859-18140 Sentence denotes The 3Cpro of picornaviruses, including FMDV [199], hepatitis A virus (HAV) [200], enteroviruses (EV71, EV-D68) and coxsackieviruses (CVB3, CV-A16, CV-A6) [201,202,203,204], antagonize innate immune signaling by targeting the critical components of the IFN pathways for proteolysis.
T273 18141-18293 Sentence denotes A newly emerged picornavirus, Seneca Valley virus (SVV), has also evolved an effective mechanism to escape host antiviral innate immune using its 3Cpro.
T274 18294-18506 Sentence denotes Moreover, 3Cpro cleaves the signaling components (MAVS, TRIF, and TANK) of type I IFN pathway and induces the degradation of the transcription factors IRF3 and IRF7 to constrain host antiviral response [205,206].
T275 18507-18599 Sentence denotes CoV nsp5 is called 3C-like protease (3CLpro), that resembles the 3Cpro of other RNA viruses.
T276 18600-18725 Sentence denotes For CoV, the polyprotein precursors (pp1a and pp1b) are mainly processed to generate mature nonstructural proteins by 3CLpro.
T277 18726-18913 Sentence denotes To date, the 3CLpro of CoVs, including PEDV and PDCoV, have been confirmed to antagonize type I IFN production by the cleavage of NF-κB essential modulator (NEMO) and STAT2 [100,207,208].
T278 18914-18996 Sentence denotes NEMO is essential for RNA virus-induced activation of NF-κB, IRF3, and IRF7 [209].
T279 18997-19107 Sentence denotes NEMO is required for MAVS-induced IKKα/β activation and is also crucial for the activation of TBK1/IKKε [149].
T280 19108-19202 Sentence denotes To establish successful infections, PEDV targets NEMO to subvert host innate immune responses.
T281 19203-19334 Sentence denotes PEDV nsp5 significantly inhibits Sendai virus (SeV)-induced IFN-β synthesis and the process depends on its protease activity [100].
T282 19335-19438 Sentence denotes Further experiments show that PEDV nsp5 inhibits RIG-I/MDA5 signaling and targets the upstream of TBK1.
T283 19439-19524 Sentence denotes The cleavage of NEMO by nsp5 is identified as responsible for this inhibitive effect.
T284 19525-19619 Sentence denotes The PEDV nsp5-mediated cleavage of NEMO efficiently blocks NEMO-mediated downstream signaling.
T285 19620-19694 Sentence denotes The cleavage site within NEMO that is grasped by nsp5 has been determined.
T286 19695-19862 Sentence denotes Of these reported immune evasion strategies employed by CoVs, the cleavage of innate immune adaptors is a particularly effective manner to disrupt antiviral responses.
T287 19863-19933 Sentence denotes Nsp5 is essential for the life cycle of PEDV and other CoVs [210,211].
T288 19934-20012 Sentence denotes It is a potential target for the development of anti-coronaviral therapeutics.
T289 20013-20185 Sentence denotes Although PEDV nsp5 does not target STAT2 mediated type Ⅰ IFN signaling pathway, PEDV nsp7 has been reported to inhibit the STAT1 and STAT2 induced activation of ISRE [212].
T290 20186-20350 Sentence denotes Nsp7 competes with Karyopherin α (KPNA1), which is an adaptor mediating nuclear translocation of ISGF3, in combination with STAT1, to block ISGF3 nuclear transport.
T291 20351-20444 Sentence denotes However, the expression and phosphorylation of STAT1 and STAT2 are not affected by PEDV nsp7.
T292 20445-20534 Sentence denotes In fact, PEDV infection degrades STAT1, leading to the inhibition of IFN signaling [170].
T293 20535-20612 Sentence denotes Therefore, other PEDV encoded proteins likely target IFNs mediated signaling.
T294 20614-20620 Sentence denotes 4.2.5.
T295 20621-20653 Sentence denotes Evasion of Viral RNA Recognition
T296 20654-20795 Sentence denotes CoVs belong to RNA viruses, which produce several RNA species, such as dsRNA intermediates and RNA with a 5′-triphosphate during replication.
T297 20796-20931 Sentence denotes These RNA intermediates are potent stimulators of PRRs and are associated with the organelles of viral RNA replication, DMVs [213,214].
T298 20932-21093 Sentence denotes DMVs formed from membranous rearrangements seem to sequester the replication intermediates using membrane-bound vesicles or invaginations to keep away from PRRs.
T299 21094-21211 Sentence denotes Therefore, the form of DMVs may be a strategy for PEDV to escape innate immune recognition in the cytosol (Figure 2).
T300 21212-21295 Sentence denotes However, whether DMVs alone are sufficient to shield RNA from PRRs remains unknown.
T301 21296-21513 Sentence denotes Besides, the replication organelles, the endoribonuclease activity and viral 5′ end RNA capping/protection mechanisms are also the critical ways of avoiding RNA recognition or protecting it from degradation [132,135].
T302 21514-21527 Sentence denotes 1) PEDV nsp15
T303 21528-21636 Sentence denotes CoV nsp15 has EndoU catalytic activity that was initially thought to play a vital role in virus replication.
T304 21637-21773 Sentence denotes However, the catalytic-defective EndoU of MHV shows only a subtle defect in viral replication compared to WT virus in fibroblasts [215].
T305 21774-21854 Sentence denotes Similar results are found for the nsp15 mutants of SARS-CoV and HCoV-229E [216].
T306 21855-21945 Sentence denotes These findings suggest that the EndoU activity of nsp15 is not required for RNA synthesis.
T307 21946-22037 Sentence denotes Recently, nsp15 has been demonstrated to act as a new IFN antagonist of CoVs [117,118,217].
T308 22038-22197 Sentence denotes Recent reports indicate that CoVs’ EndoU activity is essential for prevention of RNA recognition by MDA5, protein kinase R (PKR), and OAS/RNAse L system [118].
T309 22198-22294 Sentence denotes PKR and OAS/RNAse L recognize and destroy foreign RNA in the cytosol to defend viral infections.
T310 22295-22443 Sentence denotes To counteract the function of PKR and OAS/RNAse L, the virus hides or modifies its viral RNA, to avoid the exposure of viral RNA to these molecules.
T311 22444-22513 Sentence denotes In all CoVs, the EndoU catalytic domain in nsp15 is highly conserved.
T312 22514-22609 Sentence denotes PEDV EndoU activity has been indicated as having an antagonistic effect on IFN signaling [135].
T313 22610-22784 Sentence denotes The EndoU activity of PEDV nsp15 not only inhibits the type I IFN response in porcine macrophages, but also antagonizes the type III IFN response in porcine epithelial cells.
T314 22785-22933 Sentence denotes The replication of EndoU-mutant PEDV (icPEDV-EnUmt) is considerably impaired in porcine epithelial cells compared to the wild type PEDV (icPEDV-wt).
T315 22934-23089 Sentence denotes The icPEDV-EnUmt clearly induces early and robust type I and type III IFNs production, as well as ISGs’ expression compared with that induced by icPEDV-wt.
T316 23090-23179 Sentence denotes The EndoU-deficient PEDV infected animals also show reduced viral shedding and mortality.
T317 23180-23319 Sentence denotes These results indicate that the EndoU activity of PEDV nsp15 plays a vital role in evading host antiviral innate immunity (Figure 2) [135].
T318 23320-23333 Sentence denotes 2) PEDV nsp16
T319 23334-23385 Sentence denotes CoV nsp16 is a 2′-O-methyltransferase (2′-O-MTase).
T320 23386-23508 Sentence denotes To evade recognition by the host immune sensors, many CoVs encode methyltransferases involved in the capping of viral RNA.
T321 23509-23672 Sentence denotes This modification makes the viral RNA indistinguishable with host cell mRNA, which is important to avoid the recognition of viral RNA by MDA5 (Figure 2) [121,218].
T322 23673-23833 Sentence denotes Methylation of the two sites in the 5′ cap is catalyzed by three nsps, including nsp14 (the N-7-MTase), nsp16 (the 2′-O-MTase), and nsp10 [112,123,124,125,126].
T323 23834-23966 Sentence denotes For example, SARS-CoV nsp16 acts as a 2′-O-MTase to prevent innate immune recognition and promote viral proliferation [113,121,123].
T324 23967-24047 Sentence denotes PEDV nsp14 and nsp16 have been identified as the viral IFN antagonists [65,132].
T325 24048-24218 Sentence denotes The overexpression of nsp14 or nsp16 remarkably inhibits IFN-β production, but nsp16 appears to play a more important role in innate immunity regulation than nsp14 [132].
T326 24219-24344 Sentence denotes Nsp16 is a highly conserved methyltransferase which contains an invariant KDKE motif within the methyltransferase core [219].
T327 24345-24397 Sentence denotes This KDKE motif is required to mediate its activity.
T328 24398-24506 Sentence denotes Notably, the mutation of any of the KDKE active sit has been shown to abolish the 2′-O-MTase activity [123].
T329 24507-24675 Sentence denotes PEDV nsp16 KDKE motif plays a critical role in the inhibition of type I IFN production, suggesting the important role of the 2′-O-MTase in PEDV-mediated immune evasion.
T330 24676-24881 Sentence denotes PEDV nsp16 negatively regulates RLR-mediated signal pathway activation, and inhibits the expression of the IFN-stimulated IFIT family members (IFIT1, IFIT2, IFIT3), which in turn promotes PEDV replication.
T331 24882-25024 Sentence denotes Taken together, these results demonstrate that PEDV nsp16 negatively regulates cellular antiviral response to promote viral replication [132].
T332 25025-25204 Sentence denotes Screening inhibitors targeting the 2′-O-MTase of nsp16 might be a prominent strategy to inhibit CoV infections and develop antivirals for treatment of the diseases caused by CoVs.
T333 25205-25295 Sentence denotes Additionally, CoVs nsp14 also includes the 3′-to-5′ exoribonuclease (ExoN) activity [113].
T334 25296-25430 Sentence denotes A mutation of TGEV nsp14 ExoN generates lower levels of dsRNA than wildtype TGEV and thus triggers a reduced antiviral response [220].
T335 25431-25546 Sentence denotes Nsp14 ExoN activity is also critical for the resistance of host innate immune response in MHV-infected cells [221].
T336 25547-25688 Sentence denotes The role of nsp ExoN activity of PEDV in counteracting host antiviral response should be investigated to uncover more functions of PEDV nsps.
T337 25689-25869 Sentence denotes These data suggest that PEDV has evolved multiple evasive mechanisms to circumvent viral RNA recognition or prevent RNA degradation to establish a successful infection in the host.
T338 25871-25877 Sentence denotes 4.2.6.
T339 25878-25958 Sentence denotes PEDV Inhibits Heat Shock Protein 27 Expression to Impair Innate Immune Signaling
T340 25959-26198 Sentence denotes Heat shock protein 27 (HSP27) belongs to the small heat shock proteins family, which has been identified as a multifunctional protein involved in cytoskeletal stability, proinflammatory processes, and the inhibition of apoptosis [222,223].
T341 26199-26297 Sentence denotes Several HSPs have been reported to be implicated in PEDV infection in vitro and in vivo [224,225].
T342 26298-26481 Sentence denotes Indeed, the infection of many viruses up-regulates HSP27 expression by different mechanisms to delay cellular apoptosis, then supplies sufficient time for viral replication [226,227].
T343 26482-26607 Sentence denotes However, PEDV infection significantly induces the decreased expression of HSP27 in Vero cells [225] and MARC-145 cells [228].
T344 26608-26719 Sentence denotes HSP27 activates the phosphorylation of NF-κB, and thus promotes the mRNA expression of IFN-β in MARC-145 cells.
T345 26720-26853 Sentence denotes As HSP27 is an upstream regulator of antiviral immune signaling, overexpression of HSP27 significantly inhibits the PEDV replication.
T346 26854-26983 Sentence denotes PEDV has developed a strategy via mediating the suppression of HSP27 production to escape from host innate immune response [228].
T347 26984-27072 Sentence denotes HSP70, the most conserved HSP, is also important for the multiplication of several CoVs.
T348 27073-27182 Sentence denotes The recruitment of HSP70 is thought to be a viral survival strategy for several viruses in their hosts [229].
T349 27183-27261 Sentence denotes The relationship between HSP70 and PEDV should be exploited further in future.
T350 27263-27267 Sentence denotes 4.3.
T351 27268-27291 Sentence denotes Modulation of Apoptosis
T352 27292-27393 Sentence denotes Viral infection triggers host immune response to induce IFNs’ and inflammatory cytokines’ production.
T353 27394-27499 Sentence denotes Released IFNs elicit the expression of numerous ISGs which limit viral replication in the infected cells.
T354 27500-27632 Sentence denotes However, the release of excessive amounts of IFNs and inflammatory cytokines will lead to autoimmune and auto-inflammatory diseases.
T355 27633-27720 Sentence denotes The concomitant uncontrolled apoptosis is also one outcome that is harmful to the host.
T356 27721-27873 Sentence denotes To maintain the reaction in a proper balance, hosts have evolved a series of effective mechanisms to control the antiviral innate immune response [230].
T357 27874-27991 Sentence denotes In contrast, viruses often break this balance, causing improper apoptosis reaction, which benefits viral replication.
T358 27992-28096 Sentence denotes PEDV infects various host cells including Vero, PK-15 and Marc-145 and cause obvious cytopathic effects.
T359 28097-28195 Sentence denotes PEDV-induced apoptosis of the infected cell has been demonstrated both in vitro and in vivo [231].
T360 28196-28318 Sentence denotes Apoptosis is induced through the activation of apoptotic caspases, including caspase-2, -3, -6, -7, -8, -9, and -10 [232].
T361 28319-28562 Sentence denotes PEDV infection results in obvious caspase-3 and caspase-8 activation, as well as the cleavage of apoptosis-inducing factor mitochondria-associated 1 (AIFM1) and poly ADP-ribose polymerase (PARP), which leads to apoptotic nuclear fragmentation.
T362 28563-28743 Sentence denotes PEDV spike protein S1 significantly elicits host cell apoptosis, while the nsp1–16 and other structural proteins (M, N, E, S2, and ORF3) have none or few effects on cell apoptosis.
T363 28744-28845 Sentence denotes Therefore, S1 protein is probably the critical protein mediating the apoptosis induced by PEDV [128].
T364 28847-28851 Sentence denotes 4.4.
T365 28852-28861 Sentence denotes ER Stress
T366 28862-29009 Sentence denotes The multiple stages of CoV replication cycle are closely associated with cellular membrane compartments, especially the endoplasmic reticulum (ER).
T367 29010-29121 Sentence denotes The shape and functions of ER can be influenced by different physiological states and environmental conditions.
T368 29122-29268 Sentence denotes When protein synthesis amounts surpass the folding capacity, the accumulation of a large amount of unfolded proteins in the ER leads to ER stress.
T369 29269-29400 Sentence denotes Consequently, cells manifest a corresponding biological reaction that is widely known as the unfolded protein response (UPR) [233].
T370 29401-29608 Sentence denotes Once the UPR is induced, it alleviates the problems by host protein translation inhibition (by the transducer PKR-like ER protein kinase (PERK)-induced phosphorylation of eIF2a), stimulating protein folding.
T371 29609-29684 Sentence denotes If homeostasis cannot be re-established, apoptosis eventually is triggered.
T372 29685-29877 Sentence denotes Indeed, the activation of UPR regulates a wide variety of signaling pathways, such as apoptosis, autophagy, mitogen-activated protein (MAP) kinase activation, and innate immune response [234].
T373 29878-29956 Sentence denotes Furthermore, α-CoV and β-CoV may induce ER stress in the infected cells [235].
T374 29957-30087 Sentence denotes PEDV ORF3, as the only accessory protein encoded by PEDV, is thought to be related to virus production and virulence of PEDV [68].
T375 30088-30212 Sentence denotes A series of studies suggest that ORF3 plays multiple roles, in addition to acting as an ion channel during PEDV replication.
T376 30213-30357 Sentence denotes Recent studies show that PEDV ORF3 consists of four transmembrane domains (TMDs) and localizes in the cytoplasm in the aggregation manner [236].
T377 30358-30553 Sentence denotes ORF3 is a transmembrane protein, and the confocal microscopy analysis indicates that the aggregated ORF3 localizes in the ER to induce the ER stress associated with either apoptosis or autophagy.
T378 30554-30672 Sentence denotes However, PEDV ORF3 induces the autophagy via driving conversion of LC3-I to LC3-II, but not influencing the apoptosis.
T379 30673-30731 Sentence denotes ORF3-induced autophagy is dependent on ER stress response.
T380 30732-30875 Sentence denotes PEDV ORF3 triggers ER stress response via the up-regulation of GRP78 protein expression and the activation of the PERK-eIF2α signaling pathway.
T381 30876-31008 Sentence denotes Moreover, ORF3 protein is identified as an IFN antagonist to block IFN response by an unknown mechanism in PEDV-infected cells [65].
T382 31009-31064 Sentence denotes The functions of PEDV ORF3 should be further exploited.