LitCovid-sentences  

PMC:7281546 / 1190-52413 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T10 0-2 Sentence denotes 1.
T11 3-15 Sentence denotes Introduction
T12 16-342 Sentence denotes Porcine epidemic diarrhea virus (PEDV) is the etiological agent of porcine epidemic diarrhea (PED) that causes an acute and highly contagious enteric disease of swine characterized by vomiting, diarrhea, dehydration, and anorexia in pigs of all ages, especially resulting in severe diarrhea and high mortality rate in piglets.
T13 343-432 Sentence denotes In serious cases, outbreak of PED even leads to a mortality rate of 100% in pigs [1,2,3].
T14 433-508 Sentence denotes The causative agent of PED was first described in the 1970s in England [4].
T15 509-597 Sentence denotes In 1976, an unrecognized enteric disease was reported in several European countries [5].
T16 598-663 Sentence denotes The viral diarrhea was collectively designated “PED” in 1982 [6].
T17 664-794 Sentence denotes Endemic PED had been described in both developed and developing countries, but with a low impact on the swine industry until 2010.
T18 795-1007 Sentence denotes In 2010, outbreaks of PED caused by highly pathogenic variant PEDV strains occurred in China, and this was immediately reported in other Asian counties, causing up to 100% mortality in suckling piglets [1,7,8,9].
T19 1008-1137 Sentence denotes In April 2013, PEDV entered the United States (US) for the first time and the virulent strains spread rapidly across the US [10].
T20 1138-1271 Sentence denotes Apart from almost 100% mortality rate in suckling piglets, PEDV infection also damaged the growth performance of finishing pigs [11].
T21 1272-1425 Sentence denotes The highly pathogenic strains of PEDV spread worldwide, resulting in serious problems to the swine industry and substantial economic losses [7,10,12,13].
T22 1426-1658 Sentence denotes Vaccination used to be the main strategy to prevent and control the rate of PEDV infection [14], however, the current available PEDV vaccines cannot provide complete protection for the pigs affected by the highly pathogenic strains.
T23 1659-1823 Sentence denotes The optimal vaccines should induce efficient maternal antibodies in sows that could be transmitted to the offspring and protect neonatal suckling piglets from PEDV.
T24 1824-1920 Sentence denotes The vaccination method is critically associated with the antibodies’ induction by PEDV vaccines.
T25 1921-2012 Sentence denotes Oral vaccination with attenuated PEDV seems to be more efficacious than injectable vaccine.
T26 2013-2245 Sentence denotes Oral immunization of PEDV-seronegative pregnant sows with attenuated PEDV leads to lower mortality rate of piglets and higher amounts of IgA transferred from the sows to the offspring than that in the intramuscularly injected group.
T27 2246-2353 Sentence denotes However, the duration of virus shedding after challenge was not reduced compared to the control group [15].
T28 2354-2513 Sentence denotes The immunization dose of the virus for sows and the challenge dose of the virus for piglets significantly affected the protection against virus challenge [16].
T29 2514-2816 Sentence denotes Moreover, epidemiological studies have demonstrated that the prevalent strains causing previous PED outbreaks in China in 2010 and the recent outbreaks in North America and Asia all belong to the genogroup II (GII) PEDV and the S gene of GIIb PEDV contains typical insertion and deletion mutations [2].
T30 2817-2897 Sentence denotes Therefore, new PEDV vaccines should be developed based on these variant strains.
T31 2898-3033 Sentence denotes The biological characteristics, pathogenicity and immune protective effects of GIIb PEDV strains should be studied as soon as possible.
T32 3034-3167 Sentence denotes An inactivated vaccine based on genotype IIb strain AJ1102 developed by Wuhan Keqian company was approved for clinical trial in 2014.
T33 3168-3351 Sentence denotes In addition, the lactic acid bacteria (LAB) that have the ability to interact with the intestinal cells can be used as a potential vector for improving delivery of oral vaccines [17].
T34 3352-3540 Sentence denotes Developing the transgenic plants expressing antigenic proteins as edible vaccines to induce efficient mucosal immune responses might be a prominent strategy to prevent PEDV infection [18].
T35 3541-3658 Sentence denotes Choosing appropriate and effective adjuvants for PEDV vaccines to enhance adaptive immune response is also important.
T36 3659-3836 Sentence denotes In addition, the construction of recombinant PEDV with deletion or mutation of the immune antagonistic regions or sites is a potential strategy to develop PEDV vaccines as well.
T37 3837-3979 Sentence denotes The produced modified antigens will induce an increased and earlier immune response in pigs, compared with the antigens from wildtype viruses.
T38 3980-4337 Sentence denotes Therefore, the modification of viral antigens, the optimization of immunization methods, screening effective adjuvants, and exploiting a new generation of vaccines are promising directions for the control of PED.PEDV is classified as a coronavirus (CoV), due to its similar electron microscopic appearance and polypeptide structure to other CoVs [19,20,21].
T39 4338-4517 Sentence denotes CoVs (subfamily Coronavirinae, family Coronaviridae, order Nidovirales) are a large family of viruses that have broad host ranges and have caused global public health issues [22].
T40 4518-4741 Sentence denotes The currently known CoVs are divided into four genera, which include Alphacoronavirus (α-CoV), Betacoronavirus (β-CoV), Gammacoronavirus (γ-CoV) and Deltacoronavirus (δ-CoV), according to the genome phylogeny and serotypes.
T41 4742-4885 Sentence denotes CoVs give rise to a wide spectrum of diseases in humans and animals, but generally fall into two classes, with respiratory or enteric tropisms.
T42 4886-5177 Sentence denotes Moreover, the β-CoV genus consists of a lot of important CoVs that result in serious respiratory illnesses in humans, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the latest 2019 novel coronavirus (SARS-CoV2).
T43 5178-5276 Sentence denotes SARS-CoV resulted in an outbreak of severe respiratory disease through China in 2002–2003 [23,24].
T44 5277-5466 Sentence denotes MERS-CoV was first identified in Saudi Arabia in 2012 and is associated with severe pneumonia and acute respiratory distress syndrome (ARDS) that results in a high mortality (~35%) [25,26].
T45 5467-5639 Sentence denotes SARS-CoV2 was identified in Wuhan, China in December 2019, which leads to similar symptoms in humans as SARS-CoV, but it is more infectious to humans than SARS-CoV [27,28].
T46 5640-5895 Sentence denotes Furthermore, α-CoV genus includes porcine respiratory coronavirus (PRCV) and various enteric CoVs that lead to viral diarrhea in pigs, such as PEDV, transmissible gastroenteritis virus (TGEV), and HKU2-like porcine enteric alphacoronavirus (PEAV) [29,30].
T47 5896-6046 Sentence denotes PRCV infects the upper respiratory epithelial cells and alveolar macrophages, but the clinical manifestations caused by PRCV are not significant [31].
T48 6047-6209 Sentence denotes The swine enteric CoVs cause severe diarrhea, vomiting, and mortality in piglets, having contributed to enormous economic losses to the global swine industry [6].
T49 6210-6275 Sentence denotes PEDV is the main causative pathogen of viral diarrhea in piglets.
T50 6276-6371 Sentence denotes Over the years, significant work has been done to investigate PEDV pathogenesis and prevention.
T51 6372-6490 Sentence denotes Aminopeptidase N protein (APN, also known as CD13) is identified as a functional receptor of PEDV and TGEV [32,33,34].
T52 6491-6611 Sentence denotes APN, a 150 KD type II transmembrane glycoprotein, is mainly expressed on the apical membrane of mature enterocytes [35].
T53 6612-6714 Sentence denotes APN binds to the 477-629 amino-acid region in the C-terminal region of PEDV spike 1 (S1) protein [34].
T54 6715-6773 Sentence denotes Apart from APN, PEDV is able to bind to sialic acids [36].
T55 6774-6860 Sentence denotes It remains unknown whether PEDV uses sugar coreceptors during viral infection [34,36].
T56 6861-6974 Sentence denotes PEDV infects multiple cell lines from different species including bat and primate (human and non-human) in vitro.
T57 6975-7226 Sentence denotes The ability of PEDV to infect the cells of different species indicates that the virus utilizes the evolutionarily conserved cell components as receptors, thereby enhancing the potential for cross-species and potentially, zoonotic transmission [37,38].
T58 7227-7462 Sentence denotes The highly pathogenic variant strains of PEDV were identified in 2010 and caused a high morbidity of up to 100% in piglets, and since then, these strains become dominant, leading to most of the acute outbreaks of PED worldwide [1,7,8].
T59 7463-7581 Sentence denotes The high virulence of these strains is critically associated with the immune evasion mechanisms employed by the virus.
T60 7582-7711 Sentence denotes PEDV has evolved different strategies to delicately manipulate and damage the host innate immune system for their multiplication.
T61 7712-7909 Sentence denotes Clarification of these mechanisms is critical for understanding the host range, tropisms, pathogenesis, and for developing effective vaccines and antiviral drugs to curb the spread of PEDV in pigs.
T62 7910-8024 Sentence denotes In this review, we provide an overview of different mechanisms used by PEDV to evade host innate immune responses.
T63 8026-8028 Sentence denotes 2.
T64 8029-8054 Sentence denotes Genomic Structure of PEDV
T65 8055-8119 Sentence denotes PEDV is an enveloped, positive-sense, single-stranded RNA virus.
T66 8120-8187 Sentence denotes The PEDV genome constitution represents a standard CoV arrangement.
T67 8188-8411 Sentence denotes The viral genome is approximately 28 kb in length, containing a 5′ terminal cap, a 3′ poly (A) tail, as well as seven open reading frames (ORFs), including the ORF1a, ORF1b, S, ORF3, E, M, and N genes (Figure 1) [39,40,41].
T68 8412-8588 Sentence denotes The N terminal ORF1a and ORF1b encode two large replicase polyprotein precursors (pp1a and pp1ab), which are subsequently processed into 16 nonstructural proteins (nsp1 to 16).
T69 8589-8688 Sentence denotes ORF1a encodes pp1a which is cleaved by viral proteases into 11 nonstructural proteins (nsp1-nsp11).
T70 8689-8831 Sentence denotes The ORF1b generates five additional nonstructural proteins (nsp12–16) that are proteolytically cleaved by the viral proteases from pp1ab [42].
T71 8832-8978 Sentence denotes Nsp3 contains two papain-like protease domains (PLP1 and PLP2 or PLpro) that cleave the nsp1–4 region of the replicase polyprotein at three sites.
T72 8979-9101 Sentence denotes Nsp5, a chymotrypsin-like enzyme also known as 3C-like protease, cleaves the polyprotein at remaining cleavage sites [43].
T73 9102-9357 Sentence denotes The C terminus of viral genome contains five ORFs, encoding four structure proteins (spike protein (S), small envelope glycoprotein (E), membrane glycoprotein (M), and nucleocapsid protein (N)), as well as a hypothetical accessory protein ORF3 [44,45,46].
T74 9358-9556 Sentence denotes The 16 nsps, together with the N protein, and several host proteins, form a large replication and transcription complex (RTC) that engages in the minus-strand RNA synthesis, using viral genomic RNA.
T75 9557-9673 Sentence denotes These nsps play important roles in virion structure modification and the replication and transcription of PEDV [47].
T76 9675-9677 Sentence denotes 3.
T77 9678-9715 Sentence denotes Biological Functions of PEDV Proteins
T78 9716-9846 Sentence denotes The viral proteins of PEDV perform different biological functions during viral entry, replication cycle and propagation (Table 1).
T79 9847-10087 Sentence denotes PEDV S protein, a type I membrane glycoprotein protein located on the envelope of the virus, consists of an N-terminal signal peptide, a large extracellular region, a single transmembrane domain, as well as a short cytoplasmic tail [48,49].
T80 10088-10145 Sentence denotes The ectodomain of S protein comprises S1 and S2 subunits.
T81 10146-10278 Sentence denotes The N-terminal S1 region, containing N- and C-terminal domains (S1-NTD and S1-CTD), is mainly responsible for receptor binding [50].
T82 10279-10421 Sentence denotes The C-terminal membrane-anchored S2 region is mainly involved in triggering the fusion of the viral envelope with host cell membranes [48,49].
T83 10422-10533 Sentence denotes The interaction of the CoV S protein with its host cell surface receptor is a key determinant for host tropism.
T84 10534-10687 Sentence denotes The S1-CTD of most known members of α-CoV genus, including PEDV, interacts with aminopeptidase N (APN) to entry into the target cell [32,36,51,52,53,54].
T85 10688-10789 Sentence denotes In addition, S protein contains the epitopes that are the major targets of the neutralizing antibody.
T86 10790-10898 Sentence denotes N protein is the most abundant viral protein during the early phase of infection in CoV-infected cells [55].
T87 10899-11152 Sentence denotes Similar to the N proteins of other CoVs, the PEDV N protein has multiple functions, such as acting as a structural protein that forms nucleocapsid with viral genomic RNA, playing important roles in viral replication, transcription, and assembly [56,57].
T88 11153-11339 Sentence denotes The expression of the N protein in intestinal epithelial cells extends the S-phase of cell cycle, causes endoplasmic reticulum (ER) stress, and upregulates interleukin-8 expression [44].
T89 11340-11527 Sentence denotes Moreover, the N proteins of several α-CoVs and β-CoVs, including PEDV, PDCoV, SARS-CoV, and mouse hepatitis virus (MHV), have been identified as innate immunity antagonists [58,59,60,61].
T90 11528-11601 Sentence denotes However, the involved antagonistic mechanisms are particularly different.
T91 11602-11793 Sentence denotes PEDV M protein participates in virion assembly and virus budding through collaboration with other viral proteins, and engages in the induction of neutralizing antibodies against PEDV [62,63].
T92 11794-11849 Sentence denotes PEDV M protein is distributed throughout the cytoplasm.
T93 11850-11964 Sentence denotes It induces the cell growth retardation in intestinal epithelial cells (IEC) and arrests the cells in S-phase [64].
T94 11965-12077 Sentence denotes In addition, PEDV M protein is identified as an interferon (IFN) antagonist with an unrecognized mechanism [65].
T95 12078-12147 Sentence denotes PEDV E protein is important for the virus packaging and budding [66].
T96 12148-12264 Sentence denotes It is predominantly localized in the ER, having no effect on cell growth, cell cycle and cyclin A expression in IEC.
T97 12265-12450 Sentence denotes However, it causes ER stress and activates the nuclear factor-κB (NF-κB) pathway which is responsible for the up-regulation of IL-8 and the anti-apoptotic protein Bcl-2 expression [67].
T98 12451-12583 Sentence denotes ORF3 has been predicted to possess multiple transmembrane domains [68], while it is predominantly distributed in the cytoplasm [69].
T99 12584-12696 Sentence denotes ORF3 also detains cells at S-phase, facilitating vesicle formation, and thus promoting PEDV multiplication [69].
T100 12697-12826 Sentence denotes A recent study suggests that ORF3 interacts with S protein during PEDV assembly and consequently benefits viral replication [70].
T101 12827-13211 Sentence denotes CoV nsps play multiple roles in the synthesis or processing of viral RNA, or in virus-host interactions aiming to create an optimal environment for virus replication, such as facilitating viral entry, viral gene expression, RNA synthesis, and virion release. nsp1 is a N-terminal cleavage product of ORF1a polyprotein [71], a 9-kDa protein, that exists only in α-CoVs and β-CoVs [72].
T102 13212-13316 Sentence denotes The nsp1 of α-CoVs is not very similar to β-CoVs nsp1 with regard to sequence homology and size [73,74].
T103 13317-13455 Sentence denotes Based on the sequence alignment analysis of the genomes of different CoVs, the viral nsp1 can be regarded as a genus-specific marker [75].
T104 13456-13538 Sentence denotes Moreover, β-CoVs nsp1 has been widely reported to inhibit host protein expression.
T105 13539-13611 Sentence denotes However, the biological functions of α-CoVs nsp1 remain largely unknown.
T106 13612-13761 Sentence denotes Despite the lack of overall sequence similarity, the nsp1 of different CoVs shares a similar function to interfere with host protein expression [76].
T107 13762-13855 Sentence denotes These studies suggest the importance of nsp1 in the life cycle of different lineages of CoVs.
T108 13856-13954 Sentence denotes It is shown that TGEV nsp1 inhibits host gene expression and is critical for viral virulence [77].
T109 13955-14077 Sentence denotes PEDV nsp1 induces the degradation of CBP and NF-κB to abate IFN response [78], but the detailed mechanisms remain unclear.
T110 14078-14169 Sentence denotes The sizes and amino acid sequence identity of nsp 2 are variable among different CoVs [76].
T111 14170-14236 Sentence denotes Nsp2 of MHV and SARS-CoV are involved in viral RNA synthesis [79].
T112 14237-14345 Sentence denotes PEDV nsp2 has unknown functions in replication, and may implicate the virus-host interactions and virulence.
T113 14346-14546 Sentence denotes Nsp3 is the largest nsp protein, containing two papain-like protease (PLP1 and PLP2) domains, of which PEDV PLP2 acts as a viral deubiquitinase (DUB), to negatively regulate type I IFN signaling [80].
T114 14547-14661 Sentence denotes CoVs PLPs domains exhibit multiple functions, serving as a viral protease, DUB, as well as an IFN antagonist [81].
T115 14662-14813 Sentence denotes CoVs, like other positive-stranded RNA viruses, induce membranous rearrangements of varying morphologies that are essential for RTCs anchoring [82,83].
T116 14814-15063 Sentence denotes The CoV-induced replicative structures consist of double-membrane vesicles (DMVs) and convoluted membranes (CMs), which form a large reticulovesicular network that are critical for viral replication and transcription [84,85,86,87,88,89,90,91,92,93].
T117 15064-15230 Sentence denotes Among the CoV nsps, nsp3, nsp4, and nsp6 include the hydrophobic transmembrane domains engaging in anchoring the viral RNA synthesis components to the membranes [94].
T118 15231-15321 Sentence denotes For MERS-CoV and SARS-CoV, co-expression of nsp3 and nsp4 is required to induce DMVs [95].
T119 15322-15426 Sentence denotes SARS-CoV nsp6 has membrane proliferation ability as well, which also contributes to DMVs formation [96].
T120 15427-15494 Sentence denotes The structure and functions of α-CoV nsp3 are largely unknown [97].
T121 15495-15755 Sentence denotes Nsp4 is also a marker for CoV-induced membrane structures; some results indicate that the nsp4–10 of pp1a act as a large complex through multidomain structure or scaffold during viral RNA replication progress, before its cleavage into individual products [98].
T122 15756-15804 Sentence denotes CoVs nsp5 encodes a 3C-like proteinase (3CLpro).
T123 15805-15923 Sentence denotes The polyproteins pp1a and pp1ab are processed into individual elements of replicase by 3C-like protease and PLPs [99].
T124 15924-16037 Sentence denotes Moreover, PEDV nsp5 plays a crucial role in virus replication and also blocks host innate immune responses [100].
T125 16038-16249 Sentence denotes Crystallographic or nuclear magnetic resonance structures have shown that nsp3, nsp5, nsp7, nsp8, nsp9, and nsp10 have the PLprob and the ADP-ribose 1′′-phosphatase (ADRP) activity [101,102,103,104,105,106,107].
T126 16250-16371 Sentence denotes The crystal structure of SARS-CoV nsp9 suggests that nsp9 is dimeric and it is able to bind to single-stranded RNA [108].
T127 16372-16517 Sentence denotes The crystal structure of SARS CoV nsp10 protein suggests that nsp10 is a zinc-finger protein, which is existent exclusively in CoVs so far [107].
T128 16518-16625 Sentence denotes Moreover, nsp7–10 have RNA binding activity and nsp12 encodes a single RNA-dependent RNA polymerase (RdRp).
T129 16626-16792 Sentence denotes The biochemical characterization and crystallization of SARS CoV nsp7 and nsp8 manifests that eight copies of nsp8 and eight copies of nsp7 form a supercomplex [106].
T130 16793-16912 Sentence denotes The complex is supportive for nucleic acid binding and may be associated with the processivity of viral RdRp [102,106].
T131 16913-17095 Sentence denotes Recently, structural studies have described that the SARS-CoV nsp12 polymerase binds to the nsp7 and nsp8 complex [109] that may increase the polymerase activity of nsp12 RdRp [110].
T132 17096-17196 Sentence denotes CoV nsp13, a NTPase/helicase, is also determined to play essential roles in viral replication [111].
T133 17197-17325 Sentence denotes CoV nsp14 is a multifunctional protein with 3′-5′ exoribonuclease activity and N-7-methyltransferase [MTase] activity [112,113].
T134 17326-17399 Sentence denotes Nsp14 catalyzes the N7-methylation of Gppp-RNA to form a cap-0 structure.
T135 17400-17513 Sentence denotes CoV nsp15 encodes an endoribonuclease (EndoU), performing functions through a hexamer in many CoVs [114,115,116].
T136 17514-17600 Sentence denotes The endoribonuclease activity of nsp15 is not essential for CoV replication [117,118].
T137 17601-17854 Sentence denotes For CoVs, the 5′ end of the viral genomic RNA and subgenomic mRNA (sgmRNA) is supposed to have cap structures: an N-7 methylated guanosine nucleoside (m7GpppN) (cap 0) and a methyl group at the 2′-O-ribose position (cap 1) of the first nucleotide [119].
T138 17855-18063 Sentence denotes These cap structures enhance the initiation of translation of viral proteins, protect viral mRNAs against cellular 5′-3′-exoribonuclease and limit the recognition of viral RNA by host innate system [120,121].
T139 18064-18156 Sentence denotes Nsp13 is proposed to catalyze the first step of the 5′-capping reaction of viral RNAs [122].
T140 18157-18324 Sentence denotes The methylation of the two sites in the 5′ cap are catalyzed by three nsps; nsp14 (the N-7-MTase), nsp16 (the 2′-O-methyltransferase), and nsp10 [112,123,124,125,126].
T141 18325-18508 Sentence denotes In addition, the 3′-5′ exoribonuclease activity of nsp14 is involved in a replicative mismatch repair system during RNA synthesis, which improves the replication fidelity of CoV [42].
T142 18509-18758 Sentence denotes Although these nsps have been demonstrated to play essential roles in viral replication, transcription and/or post-translational polyprotein processing [127], the nsp12–16 of PEDV and other CoVs are poorly characterized to date, except for SARS-CoV.
T143 18760-18762 Sentence denotes 4.
T144 18763-18800 Sentence denotes Innate Immunity during PEDV Infection
T145 18801-19037 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 19038-19255 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 19257-19261 Sentence denotes 4.1.
T148 19262-19287 Sentence denotes Overview of IFN Responses
T149 19288-19620 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 19621-20099 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 20100-20232 Sentence denotes In the cytosol, the formation of specific secondary structure of viral RNA is closely related to viral RNA delivery and replication.
T152 20233-20432 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 20433-20630 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 20631-20807 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 20808-21097 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 21098-21295 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 21296-21511 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 21512-21644 Sentence denotes IKKs (IKKα, IKKβ and IKKγ) phosphorylate NF-κB inhibitor (IκB), leading to the ubiquitination of IκB and its subsequent degradation.
T159 21645-21763 Sentence denotes NF-κB is then activated and translocated into the nucleus to turn on the expression of proinflammatory and type I IFN.
T160 21764-21957 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 21958-22112 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 22113-22256 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 22257-22367 Sentence denotes MITA interacts with the TRAP complex, which may be involved in recruiting TBK1 and IKKε to phosphorylate IRF3.
T164 22368-22468 Sentence denotes Ubiquitination and deubiquitination are decisive in the regulation of RLR pathways activation [150].
T165 22469-22605 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 22606-22742 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 22743-22808 Sentence denotes This modification is crucial for RIG-I to recruit MAVS [154,155].
T168 22809-23012 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 23013-23183 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 23184-23280 Sentence denotes Ubiquitination and deubiquitination are in a dynamic equilibrium to maintain immune homeostasis.
T171 23281-23400 Sentence denotes Type I IFNs are secreted by secretory cells and peripheral cells through self-secretion or paracrine secretion manners.
T172 23401-23639 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 23640-23852 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 23853-24008 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 24009-24169 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 24170-24233 Sentence denotes Three types of IFNs (types I, II and III) have been identified.
T177 24234-24284 Sentence denotes Type I and type II IFNs have been widely reported.
T178 24285-24317 Sentence denotes Type II IFNs only contain IFN-γ.
T179 24318-24477 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 24478-24562 Sentence denotes IFN-γ binds to the type II IFN receptor composed of two subunits, IFNGR1 and IFNGR2.
T181 24563-24628 Sentence denotes IFNGR1 and IFNGR2 induce the formation of STAT1-STAT1 homodimers.
T182 24629-24810 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 24811-24943 Sentence denotes Type III IFNs have been explored in recent years, to unravel the underlying mechanisms that manipulate host innate immune responses.
T184 24944-25069 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 25070-25176 Sentence denotes Their expression profiles, signaling pathways, and gene expression programs resemble those of type I IFNs.
T186 25177-25329 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 25330-25574 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 25575-25674 Sentence denotes The promoter of IFN-λ1 includes more NF-κB binding sites compared with in the IFN-β promoter [164].
T189 25675-25798 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 25799-26029 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 26030-26254 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 26256-26260 Sentence denotes 4.2.
T193 26261-26294 Sentence denotes Immune Evasion Mechanisms of PEDV
T194 26295-26414 Sentence denotes Induction of IFN-α/β is the most rapid and effective mechanism for hosts to initiate antiviral innate immune responses.
T195 26415-26471 Sentence denotes SARS-CoV, MHV and many other CoVs are sensitive to IFNs.
T196 26472-26628 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 26629-26795 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 26796-27156 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 27157-27348 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 27349-27454 Sentence denotes This explains why only weak IFNs’ and cytokines’ expression is detected in PEDV-infected cells [169,170].
T201 27456-27462 Sentence denotes 4.2.1.
T202 27463-27477 Sentence denotes PEDV N Protein
T203 27478-27651 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 27652-27806 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 27807-28004 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 28005-28195 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 28196-28292 Sentence denotes Moreover, the effect of PEDV N protein on type III IFN production has also been evaluated [168].
T208 28293-28535 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 28536-28674 Sentence denotes Recent studies show that SARS-CoV N protein inhibits type I IFN production through suppressing TRIM25-mediated RIG-I ubiquitination [171].
T210 28675-28758 Sentence denotes The MERS-CoV N protein also blocks IFN production by interacting with TRIM25 [171].
T211 28759-28991 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 28992-29102 Sentence denotes These results indicate the important function of the CoVs N protein in modulating host innate immune response.
T213 29103-29172 Sentence denotes Whether PEDV N protein targets TRIM25 or PACT should be investigated.
T214 29173-29383 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 29384-29453 Sentence denotes CoV N protein is a vital viral protein involved in virus replication.
T216 29454-29649 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 29650-29726 Sentence denotes In the host cells, a large number of host proteins reveal various functions.
T218 29727-29806 Sentence denotes However, for the virus, the genome only encodes several limited viral proteins.
T219 29807-29919 Sentence denotes Therefore, these viral proteins have to be multifunctional, which is pivotal to virus replication and existence.
T220 29921-29927 Sentence denotes 4.2.2.
T221 29928-29937 Sentence denotes PEDV nsp1
T222 29938-30098 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 30099-30246 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 30247-30406 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 30407-30544 Sentence denotes SARS-CoV nsp1 also blocks the expression of IFN-inducible genes, by restraining the signal transduction during virus infection [181,182].
T226 30545-30635 Sentence denotes The TGEV nsp1 considerably suppresses host protein expression during viral infection [77].
T227 30636-30761 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 30762-30990 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 30991-31108 Sentence denotes PEDV nsp1 has been identified as an IFN antagonist, which constrains poly (I:C)-induced IFN-β promoter activity [65].
T230 31109-31268 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 31269-31423 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 31424-31564 Sentence denotes CBP/p300, the transcription co-activator cAMP responsive element binding protein (CREB), forms a complex with the activated IRF3 in nucleus.
T233 31565-31804 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 31805-31870 Sentence denotes Therefore, PEDV nsp1 blocks type I IFN production in the nucleus.
T235 31871-32003 Sentence denotes Activated NF-κB induces the production of type I IFNs and proinflammatory cytokines and is important for inhibiting viral infection.
T236 32004-32153 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 32154-32348 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 32349-32507 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 32508-32574 Sentence denotes Among these antagonists, nsp1 is the most potent suppressor [130].
T240 32575-32715 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 32716-32798 Sentence denotes The conserved residues of PEDV nsp1 protein are crucial for IFN suppression [130].
T242 32799-32944 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 32946-32952 Sentence denotes 4.2.3.
T244 32953-32957 Sentence denotes PLP2
T245 32958-33316 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 33317-33472 Sentence denotes During viral infection, a reciprocatory action (occurrence of ubiquitination and deubiquitination) helps maintain the homeostasis of host immune responses.
T247 33473-33583 Sentence denotes Hence, deubiquitinases (DUBs) are indispensable in the regulation of virus-induced type I IFN signaling [188].
T248 33584-33695 Sentence denotes Many host DUBs have been reported engaging in the regulation of innate immune signaling pathways [189,190,191].
T249 33696-33841 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 33842-34085 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 34086-34198 Sentence denotes To counteract host antiviral response, CoVs likely take advantage of DUB activity to break host innate immunity.
T252 34199-34346 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 34347-34475 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 34476-34645 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 34646-34791 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 34792-34955 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 34956-35076 Sentence denotes As expected, the interference with the ubiquitination of RIG-I and STING by PLP2 clearly benefits PEDV replication [80].
T258 35077-35137 Sentence denotes PEDV nsp3 contains two core domains of PLPs (PLPl and PLP2).
T259 35138-35241 Sentence denotes It is determined that PEDV PLP2, but not PLP1, inhibits the IFN-β promoter activation in HEK293T cells.
T260 35242-35313 Sentence denotes The DUB activity of PLP2 is highly dependent on its catalytic activity.
T261 35314-35495 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 35496-35676 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 35677-35746 Sentence denotes PEDV infection degrades p53 by upregulation of MDM2 expression [198].
T264 35747-35872 Sentence denotes PEDV PLP2 may be responsible for targeting the p53 pathway and inhibiting p53-dependent apoptosis, leading to immune evasion.
T265 35873-36046 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 36047-36162 Sentence denotes It suggests that different viral proteins are involved in the deubiquitination of host proteins for different CoVs.
T267 36163-36317 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 36318-36492 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 36494-36500 Sentence denotes 4.2.4.
T270 36501-36510 Sentence denotes PEDV nsp5
T271 36511-36618 Sentence denotes Notably, 3Cpro is a critical IFN antagonistic protein identified in multiple different families of viruses.
T272 36619-36900 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 36901-37053 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 37054-37266 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 37267-37359 Sentence denotes CoV nsp5 is called 3C-like protease (3CLpro), that resembles the 3Cpro of other RNA viruses.
T276 37360-37485 Sentence denotes For CoV, the polyprotein precursors (pp1a and pp1b) are mainly processed to generate mature nonstructural proteins by 3CLpro.
T277 37486-37673 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 37674-37756 Sentence denotes NEMO is essential for RNA virus-induced activation of NF-κB, IRF3, and IRF7 [209].
T279 37757-37867 Sentence denotes NEMO is required for MAVS-induced IKKα/β activation and is also crucial for the activation of TBK1/IKKε [149].
T280 37868-37962 Sentence denotes To establish successful infections, PEDV targets NEMO to subvert host innate immune responses.
T281 37963-38094 Sentence denotes PEDV nsp5 significantly inhibits Sendai virus (SeV)-induced IFN-β synthesis and the process depends on its protease activity [100].
T282 38095-38198 Sentence denotes Further experiments show that PEDV nsp5 inhibits RIG-I/MDA5 signaling and targets the upstream of TBK1.
T283 38199-38284 Sentence denotes The cleavage of NEMO by nsp5 is identified as responsible for this inhibitive effect.
T284 38285-38379 Sentence denotes The PEDV nsp5-mediated cleavage of NEMO efficiently blocks NEMO-mediated downstream signaling.
T285 38380-38454 Sentence denotes The cleavage site within NEMO that is grasped by nsp5 has been determined.
T286 38455-38622 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 38623-38693 Sentence denotes Nsp5 is essential for the life cycle of PEDV and other CoVs [210,211].
T288 38694-38772 Sentence denotes It is a potential target for the development of anti-coronaviral therapeutics.
T289 38773-38945 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 38946-39110 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 39111-39204 Sentence denotes However, the expression and phosphorylation of STAT1 and STAT2 are not affected by PEDV nsp7.
T292 39205-39294 Sentence denotes In fact, PEDV infection degrades STAT1, leading to the inhibition of IFN signaling [170].
T293 39295-39372 Sentence denotes Therefore, other PEDV encoded proteins likely target IFNs mediated signaling.
T294 39374-39380 Sentence denotes 4.2.5.
T295 39381-39413 Sentence denotes Evasion of Viral RNA Recognition
T296 39414-39555 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 39556-39691 Sentence denotes These RNA intermediates are potent stimulators of PRRs and are associated with the organelles of viral RNA replication, DMVs [213,214].
T298 39692-39853 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 39854-39971 Sentence denotes Therefore, the form of DMVs may be a strategy for PEDV to escape innate immune recognition in the cytosol (Figure 2).
T300 39972-40055 Sentence denotes However, whether DMVs alone are sufficient to shield RNA from PRRs remains unknown.
T301 40056-40273 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 40274-40287 Sentence denotes 1) PEDV nsp15
T303 40288-40396 Sentence denotes CoV nsp15 has EndoU catalytic activity that was initially thought to play a vital role in virus replication.
T304 40397-40533 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 40534-40614 Sentence denotes Similar results are found for the nsp15 mutants of SARS-CoV and HCoV-229E [216].
T306 40615-40705 Sentence denotes These findings suggest that the EndoU activity of nsp15 is not required for RNA synthesis.
T307 40706-40797 Sentence denotes Recently, nsp15 has been demonstrated to act as a new IFN antagonist of CoVs [117,118,217].
T308 40798-40957 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 40958-41054 Sentence denotes PKR and OAS/RNAse L recognize and destroy foreign RNA in the cytosol to defend viral infections.
T310 41055-41203 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 41204-41273 Sentence denotes In all CoVs, the EndoU catalytic domain in nsp15 is highly conserved.
T312 41274-41369 Sentence denotes PEDV EndoU activity has been indicated as having an antagonistic effect on IFN signaling [135].
T313 41370-41544 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 41545-41693 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 41694-41849 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 41850-41939 Sentence denotes The EndoU-deficient PEDV infected animals also show reduced viral shedding and mortality.
T317 41940-42079 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 42080-42093 Sentence denotes 2) PEDV nsp16
T319 42094-42145 Sentence denotes CoV nsp16 is a 2′-O-methyltransferase (2′-O-MTase).
T320 42146-42268 Sentence denotes To evade recognition by the host immune sensors, many CoVs encode methyltransferases involved in the capping of viral RNA.
T321 42269-42432 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 42433-42593 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 42594-42726 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 42727-42807 Sentence denotes PEDV nsp14 and nsp16 have been identified as the viral IFN antagonists [65,132].
T325 42808-42978 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 42979-43104 Sentence denotes Nsp16 is a highly conserved methyltransferase which contains an invariant KDKE motif within the methyltransferase core [219].
T327 43105-43157 Sentence denotes This KDKE motif is required to mediate its activity.
T328 43158-43266 Sentence denotes Notably, the mutation of any of the KDKE active sit has been shown to abolish the 2′-O-MTase activity [123].
T329 43267-43435 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 43436-43641 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 43642-43784 Sentence denotes Taken together, these results demonstrate that PEDV nsp16 negatively regulates cellular antiviral response to promote viral replication [132].
T332 43785-43964 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 43965-44055 Sentence denotes Additionally, CoVs nsp14 also includes the 3′-to-5′ exoribonuclease (ExoN) activity [113].
T334 44056-44190 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 44191-44306 Sentence denotes Nsp14 ExoN activity is also critical for the resistance of host innate immune response in MHV-infected cells [221].
T336 44307-44448 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 44449-44629 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 44631-44637 Sentence denotes 4.2.6.
T339 44638-44718 Sentence denotes PEDV Inhibits Heat Shock Protein 27 Expression to Impair Innate Immune Signaling
T340 44719-44958 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 44959-45057 Sentence denotes Several HSPs have been reported to be implicated in PEDV infection in vitro and in vivo [224,225].
T342 45058-45241 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 45242-45367 Sentence denotes However, PEDV infection significantly induces the decreased expression of HSP27 in Vero cells [225] and MARC-145 cells [228].
T344 45368-45479 Sentence denotes HSP27 activates the phosphorylation of NF-κB, and thus promotes the mRNA expression of IFN-β in MARC-145 cells.
T345 45480-45613 Sentence denotes As HSP27 is an upstream regulator of antiviral immune signaling, overexpression of HSP27 significantly inhibits the PEDV replication.
T346 45614-45743 Sentence denotes PEDV has developed a strategy via mediating the suppression of HSP27 production to escape from host innate immune response [228].
T347 45744-45832 Sentence denotes HSP70, the most conserved HSP, is also important for the multiplication of several CoVs.
T348 45833-45942 Sentence denotes The recruitment of HSP70 is thought to be a viral survival strategy for several viruses in their hosts [229].
T349 45943-46021 Sentence denotes The relationship between HSP70 and PEDV should be exploited further in future.
T350 46023-46027 Sentence denotes 4.3.
T351 46028-46051 Sentence denotes Modulation of Apoptosis
T352 46052-46153 Sentence denotes Viral infection triggers host immune response to induce IFNs’ and inflammatory cytokines’ production.
T353 46154-46259 Sentence denotes Released IFNs elicit the expression of numerous ISGs which limit viral replication in the infected cells.
T354 46260-46392 Sentence denotes However, the release of excessive amounts of IFNs and inflammatory cytokines will lead to autoimmune and auto-inflammatory diseases.
T355 46393-46480 Sentence denotes The concomitant uncontrolled apoptosis is also one outcome that is harmful to the host.
T356 46481-46633 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 46634-46751 Sentence denotes In contrast, viruses often break this balance, causing improper apoptosis reaction, which benefits viral replication.
T358 46752-46856 Sentence denotes PEDV infects various host cells including Vero, PK-15 and Marc-145 and cause obvious cytopathic effects.
T359 46857-46955 Sentence denotes PEDV-induced apoptosis of the infected cell has been demonstrated both in vitro and in vivo [231].
T360 46956-47078 Sentence denotes Apoptosis is induced through the activation of apoptotic caspases, including caspase-2, -3, -6, -7, -8, -9, and -10 [232].
T361 47079-47322 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 47323-47503 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 47504-47605 Sentence denotes Therefore, S1 protein is probably the critical protein mediating the apoptosis induced by PEDV [128].
T364 47607-47611 Sentence denotes 4.4.
T365 47612-47621 Sentence denotes ER Stress
T366 47622-47769 Sentence denotes The multiple stages of CoV replication cycle are closely associated with cellular membrane compartments, especially the endoplasmic reticulum (ER).
T367 47770-47881 Sentence denotes The shape and functions of ER can be influenced by different physiological states and environmental conditions.
T368 47882-48028 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 48029-48160 Sentence denotes Consequently, cells manifest a corresponding biological reaction that is widely known as the unfolded protein response (UPR) [233].
T370 48161-48368 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 48369-48444 Sentence denotes If homeostasis cannot be re-established, apoptosis eventually is triggered.
T372 48445-48637 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 48638-48716 Sentence denotes Furthermore, α-CoV and β-CoV may induce ER stress in the infected cells [235].
T374 48717-48847 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 48848-48972 Sentence denotes A series of studies suggest that ORF3 plays multiple roles, in addition to acting as an ion channel during PEDV replication.
T376 48973-49117 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 49118-49313 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 49314-49432 Sentence denotes However, PEDV ORF3 induces the autophagy via driving conversion of LC3-I to LC3-II, but not influencing the apoptosis.
T379 49433-49491 Sentence denotes ORF3-induced autophagy is dependent on ER stress response.
T380 49492-49635 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 49636-49768 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 49769-49824 Sentence denotes The functions of PEDV ORF3 should be further exploited.
T383 49826-49828 Sentence denotes 5.
T384 49829-49840 Sentence denotes Conclusions
T385 49841-49987 Sentence denotes PEDV has caused epidemic and endemic infections in pig populations in many countries and has become a major economic threat to the swine industry.
T386 49988-50196 Sentence denotes Previous studies have identified viral factors that target key signaling molecules in the RLRs’ pathways, as well as viral factors that target the downstream signaling pathways responsible for ISGs induction.
T387 50197-50312 Sentence denotes Of the 23 PEDV-encoded proteins, at least 10 viral proteins have been identified as type I IFN antagonists [65,78].
T388 50313-50463 Sentence denotes The mechanisms utilized by PEDV nsp1, PLP2, nsp5, and N protein to antagonize type I IFN production have been clarified (Figure 3, [58,65,78,80,129]).
T389 50464-50577 Sentence denotes However, the specific mechanisms of other viral proteins to inhibit type I IFN production remain largely unknown.
T390 50578-50658 Sentence denotes At present, 11 PEDV proteins have been identified as type III IFNs’ antagonists.
T391 50659-50844 Sentence denotes The suppression of type III IFN signaling by N protein, nsp1, as well as nsp15, has been reported, while the mechanisms utilized by these viral proteins need to be further investigated.
T392 50845-51035 Sentence denotes In addition, the CoVs replication cycle may induce the changes of ER stress, cell apoptosis, autophagy pathways, which contain intricate virus-host interactions and cross-talk relationships.
T393 51036-51138 Sentence denotes Thus, more researches for PEDV are needed to truly reflect viral evasions from innate immune defenses.
T394 51139-51223 Sentence denotes The findings of PEDV-host interactions will help prevent and control PEDV spreading.