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LitCovid-PD-FMA-UBERON

LitCovid-PD-MONDO

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T101","span":{"begin":1211,"end":1219},"obj":"Disease"},{"id":"T102","span":{"begin":1663,"end":1679},"obj":"Disease"},{"id":"T103","span":{"begin":3233,"end":3241},"obj":"Disease"},{"id":"T104","span":{"begin":4511,"end":4521},"obj":"Disease"},{"id":"T105","span":{"begin":5233,"end":5242},"obj":"Disease"}],"attributes":[{"id":"A101","pred":"mondo_id","subj":"T101","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A102","pred":"mondo_id","subj":"T102","obj":"http://purl.obolibrary.org/obo/MONDO_0005108"},{"id":"A103","pred":"mondo_id","subj":"T103","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A104","pred":"mondo_id","subj":"T104","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A105","pred":"mondo_id","subj":"T105","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"}],"text":"4.2.5. Evasion of Viral RNA Recognition\nCoVs belong to RNA viruses, which produce several RNA species, such as dsRNA intermediates and RNA with a 5′-triphosphate during replication. These RNA intermediates are potent stimulators of PRRs and are associated with the organelles of viral RNA replication, DMVs [213,214]. DMVs formed from membranous rearrangements seem to sequester the replication intermediates using membrane-bound vesicles or invaginations to keep away from PRRs. Therefore, the form of DMVs may be a strategy for PEDV to escape innate immune recognition in the cytosol (Figure 2). However, whether DMVs alone are sufficient to shield RNA from PRRs remains unknown. 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].\n1) PEDV nsp15\nCoV nsp15 has EndoU catalytic activity that was initially thought to play a vital role in virus replication. However, the catalytic-defective EndoU of MHV shows only a subtle defect in viral replication compared to WT virus in fibroblasts [215]. Similar results are found for the nsp15 mutants of SARS-CoV and HCoV-229E [216]. These findings suggest that the EndoU activity of nsp15 is not required for RNA synthesis. Recently, nsp15 has been demonstrated to act as a new IFN antagonist of CoVs [117,118,217]. 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]. PKR and OAS/RNAse L recognize and destroy foreign RNA in the cytosol to defend viral infections. 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. In all CoVs, the EndoU catalytic domain in nsp15 is highly conserved. PEDV EndoU activity has been indicated as having an antagonistic effect on IFN signaling [135]. 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. The replication of EndoU-mutant PEDV (icPEDV-EnUmt) is considerably impaired in porcine epithelial cells compared to the wild type PEDV (icPEDV-wt). 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. The EndoU-deficient PEDV infected animals also show reduced viral shedding and mortality. These results indicate that the EndoU activity of PEDV nsp15 plays a vital role in evading host antiviral innate immunity (Figure 2) [135].\n2) PEDV nsp16\nCoV nsp16 is a 2′-O-methyltransferase (2′-O-MTase). To evade recognition by the host immune sensors, many CoVs encode methyltransferases involved in the capping of viral RNA. 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]. 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]. For example, SARS-CoV nsp16 acts as a 2′-O-MTase to prevent innate immune recognition and promote viral proliferation [113,121,123]. PEDV nsp14 and nsp16 have been identified as the viral IFN antagonists [65,132]. 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]. Nsp16 is a highly conserved methyltransferase which contains an invariant KDKE motif within the methyltransferase core [219]. This KDKE motif is required to mediate its activity. Notably, the mutation of any of the KDKE active sit has been shown to abolish the 2′-O-MTase activity [123]. 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. 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. Taken together, these results demonstrate that PEDV nsp16 negatively regulates cellular antiviral response to promote viral replication [132]. 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. Additionally, CoVs nsp14 also includes the 3′-to-5′ exoribonuclease (ExoN) activity [113]. A mutation of TGEV nsp14 ExoN generates lower levels of dsRNA than wildtype TGEV and thus triggers a reduced antiviral response [220]. Nsp14 ExoN activity is also critical for the resistance of host innate immune response in MHV-infected cells [221]. The role of nsp ExoN activity of PEDV in counteracting host antiviral response should be investigated to uncover more functions of PEDV nsps. 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."}

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

LitCovid-sentences

2_test

LitCovid-PubTator

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