LitCovid-sentences  

PMC:7736111 / 5371-17251 JSONTXT 3 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T32 0-43 Sentence denotes Nucleic Acid Sensors in Antiviral Signaling
T33 44-199 Sentence denotes SARS-CoV-2, like its predecessor SARS-CoV, employs spike (S) protein to enter into the eukaryotic cells by binding to the surface-expressed ACE2 receptors.
T34 200-527 Sentence denotes Upon binding, S protein priming takes place by the membrane expressed protease TMPRSS2 or endosomal proteases such as cathepsin, elastase, and furin (which is specific to SARS-CoV-2) to induce fusion between the viral and host cell membrane (Hoffmann et al., 2020; Shang et al., 2020; Walls et al., 2020; Wang Q. et al., 2020).
T35 528-805 Sentence denotes Following these well-coordinated events, viral genetic material will release in a biphasic manner, i.e. either by direct fusion with the plasma membrane or by following the endocytic route as shown previously for SARS-CoV (Belouzard et al., 2012; Shang et al., 2020; Figure 1).
T36 806-1224 Sentence denotes An increasing list of cell types appear directly infected by the SARS-CoV-2, which include the alveolar epithelial type II cell (ATII) as the principal targets, and other cell types lining various tissues such as bronchial epithelial cells in lungs, goblet cells in the nasal cavity, macrophages, esophageal cells, pancreatic β-cells, and gastrointestinal epithelial cells (Li M.Y. et al., 2020; Sungnak et al., 2020).
T37 1225-1319 Sentence denotes All these cell types express the S protein target receptor ACE2, albeit with lower expression.
T38 1320-1467 Sentence denotes However, ATII cells remain the predominant targets for SARS-CoV-2 as for SARS-CoV, which are involved in the sensing of the various viral proteins.
T39 1468-1533 Sentence denotes FIGURE 1 Proposed model of SARS-CoV-2 entry into the host cells.
T40 1534-1787 Sentence denotes Based on available literature on SARS-CoV and recent findings on SARS-CoV-2, we suggest two different mechanisms that can be employed by SARS-CoV-2 to enter into the ACE2 expressing cells. (1) Initially the virus may use the cell membrane mode of entry.
T41 1788-2031 Sentence denotes The first step is the binding of the spike protein of the virus with ACE2 receptors expressed on the plasma membrane of host cells. (2) The attachment with ACE2 is followed by the cleavage of S protein by membrane bound proteases like TMPRSS2.
T42 2032-2614 Sentence denotes TMPRSS2 cleaves the membrane bound virus at both S1/S2 boundary as well as at S2’ site. (3) This activates the fusion machinery, and subsequently, the viral membrane fuses with the host cell plasma membrane. (4) This leads to release of the viral nucleocapsid into the cytoplasm. (5) The replication, assembly, and maturation of virus takes places in the cytoplasm. (6) Before dissemination, SARS-CoV-2 may also undergo pre-activation in the golgi apparatus by furin proteases. (7) The fully mature and pre-activated SARS-CoV-2 eventually disseminates from host cells by exocytosis.
T43 2615-2744 Sentence denotes During subsequent infection cycles, the virus may utilize either cell membrane or (8–11) the more probable endocytic entry route.
T44 2745-3107 Sentence denotes In the endocytic mode of entry, (8) after attachment with ACE2, (9) the virus gets endocytosed and (10) then processed at the S2’ region by endosomal proteases like cathepsins, to activate membrane fusion. (11) Finally, the viral components are released into the cytoplasm by fusion of the viral membranes with endosomal membrane, leading to repeat of the cycle.
T45 3108-3330 Sentence denotes Preceding studies on human infecting coronaviruses (CoVs) have demonstrated a critical role of nucleic acid-sensing (NAS) pathways in recognizing various components of these viruses to initiate an early antiviral response.
T46 3331-3479 Sentence denotes Whereas, potent inhibitory mechanisms are developed by CoVs to prevent or delay early antiviral responses (Rose et al., 2010; Adedeji et al., 2013).
T47 3480-3578 Sentence denotes These inhibitory signals affect a range of host defense pathways to allow the propagation of CoVs.
T48 3579-3681 Sentence denotes Some inhibitory signals may even activate cell death pathway to induce a robust proinflammatory state.
T49 3682-4009 Sentence denotes Studies from in vitro cell culture, animal models, and patients who have successfully recovered from SARS-CoV infection have provided detailed molecular insights about signaling molecules implicated in virus-host interaction that may also serve as a model to understand a similar process in SARS-CoV-2 (Totura and Baric, 2012).
T50 4010-4217 Sentence denotes After release into the cytoplasm, the ssRNA viral genomes of SARS-CoV and SARS-CoV-2 proceed to replication via a double-stranded RNA (dsRNA) intermediate state (Adedeji et al., 2012; Cascella et al., 2020).
T51 4218-4382 Sentence denotes Both ssRNA and dsRNA act as pathogen-associated molecular patterns (PAMPs) which are recognized by pathogen recognition receptors (PRRs; Leiva-Juárez et al., 2018).
T52 4383-4565 Sentence denotes ATII cells are known to express key endogenous PRRs like Toll-like receptors (TLRs), cyclic GMP–AMP synthase (cGAS); and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs).
T53 4566-4770 Sentence denotes Among these, cytosolic RLRs and endosomal TLRs (TLR3, TLR7, TLR8, TLR9) have a prominent role in initiating the antiviral response by sensing RNA from SARS-CoVs (Lester and Li, 2014; Chan and Gack, 2016).
T54 4771-5024 Sentence denotes RLRs are a complex of sensor proteins that include RIG-I, melanoma differentiation-associated gene 5 (MDA5), and the more recently discovered probable ATP-dependent RNA helicase DHX58 (also known as LGP2) (Jiang et al., 2011; Leiva-Juárez et al., 2018).
T55 5025-5130 Sentence denotes RIG-I binds to 5’-PPP RNA and short dsRNA, while MDA5 binds to longer RNA fragments (Huang et al., 2014).
T56 5131-5280 Sentence denotes Binding of pathogenic RNAs induces conformational changes in RIG-I and MDA5, and after that post-translational modifications activate these proteins.
T57 5281-5639 Sentence denotes Importantly, RIG-I is activated by E3 ligase tripartite motif protein 25 (TRIM25) via polyubiquitination at K172 residue (Sanchez et al., 2016); MDA5 is proteolytically inactivated by the polyubiquitination mediated by poly (rC) binding protein 2 (PCBP2) with assistance from AIP4/ITCH (Atrophin 1 Interacting Protein 4; also called ITCH) (You et al., 2009).
T58 5640-5731 Sentence denotes LGP2 acts as a facilitator to enhance viral sensing by RIG-1 and MDA5 (Satoh et al., 2010).
T59 5732-5967 Sentence denotes Activated RIG-I and MDA5 then mount the downstream signaling cascade via centrally placed mitochondrial antiviral signaling protein (MAVS) and eventually lead to the coordinated activation of IRF3/IRF7 transcription factors (Figure 2).
T60 5968-6148 Sentence denotes Activated IRF3/7 translocates to the nucleus and induces expression of IFNs via IFN-stimulated response element (ISRE) reviewed by West et al. (2011) and Rehwinkel and Gack (2020).
T61 6149-6370 Sentence denotes Thus, centrally placed MAVS activation induces expression of IFN genes via IRF3 and IRF7 pathways and recruitment of other innate immune cells, majorly by proinflammatory molecules secreted via NF κB signaling (Figure 2).
T62 6371-6554 Sentence denotes Similarly, activation of endogenous TLR pathway induces expression of IFN type I, type III, and more specifically, proinflammatory molecules via the NF κB pathway (Gong et al., 2020).
T63 6555-6772 Sentence denotes Blocking of either IRF3/7 or NF κB pathway has a detrimental effect on host cells that invariably allows propagation of the virus (Lazear et al., 2013; Schmitz et al., 2014; Totura et al., 2015; Chiang and Liu, 2019).
T64 6773-6918 Sentence denotes In animal studies, mice that are deficient in TLR signaling exhibit robust infection and severe pathological condition during SARS-CoV infection.
T65 6919-7058 Sentence denotes TLR3 and TLR4 knockout mice exhibited increased viral titers associated with lung damage and a higher mortality rate (Totura et al., 2015).
T66 7059-7268 Sentence denotes Mice with a knockout of myeloid differentiation primary response 88 (MYD88), which acts downstream of TLR signaling had increased damage to the lung parenchyma with a 90% mortality rate (Sheahan et al., 2008).
T67 7269-7555 Sentence denotes Conversely, activation of endogenous TLR signaling by TLR7, TLR8, and TLR9 or cell surface-expressed TLR4 signaling was associated with a significant decrease in viral propagation, attenuated lung damage, and increased the survival rate in SARS-CoV infected animals (Zhao et al., 2012).
T68 7556-7704 Sentence denotes These findings thus point to an integral role of these molecular sensors in mounting early protective antiviral response and aiding viral clearance.
T69 7705-7919 Sentence denotes FIGURE 2 Molecular and signaling pathway implicated in host cell antiviral response. (A) After the viral contents are released into the cytoplasm, the viral RNA is recognized by host cell NASs like RIG-I and MDA5.
T70 7920-8040 Sentence denotes Counter-defense may be provided by the viral proteins, NSP14 and NSP16 to shield the viral RNA from sensing by the NASs.
T71 8041-8183 Sentence denotes However, if successfully recognized, RIG-I and MDA5 get activated and subsequently activate the centrally placed MAVS located on mitochondria.
T72 8184-8251 Sentence denotes MAVS acts as a molecular adaptor that further recruits TRAF2/3/5/6.
T73 8252-8380 Sentence denotes Association of the type of TRAF with MAVS is suggested to determine the type of downstream signaling, i.e., IRF3/7 and/or NF-κB.
T74 8381-8474 Sentence denotes At the MAVS junction, the association of TRAF5/6 with TRADD, FADD, and RIPK1 activates NF-κB.
T75 8475-8644 Sentence denotes Whereas, binding of MAVS with STING activates TBK1 and IKKε by interacting with TRAF2/3, which eventually results in the activation of IRF3 and IRF7 (Chen et al., 2014).
T76 8645-8936 Sentence denotes Activated IRF3, IRF7, and NF-κB translocate to the nucleus and induce the expression of IFN genes. (B) The transcribed IFNs act on the respective IFN receptors (IFNRs) present on the host cells as well as on other innate immune cells, thus signaling in a both autocrine and paracrine manner.
T77 8937-9046 Sentence denotes Signaling via IFNRs activates the JAK/STAT signaling pathway and subsequently induces the expression of ISGs.
T78 9047-9120 Sentence denotes These molecular events were recently reviewed (Rehwinkel and Gack, 2020).
T79 9121-9180 Sentence denotes ISGs transcribed will eventually inhibit viral propagation.
T80 9181-9322 Sentence denotes However, SARS-CoV and likely SARS-CoV-2 have developed counter-defense mechanisms to interfere at various steps in the NAS signaling pathway.
T81 9323-9385 Sentence denotes NSP4a inhibits TRIM25, which is required for RIG-I activation.
T82 9386-9612 Sentence denotes N protein inhibits MDA5, NSP14 inhibits MAVS, ORF9b inhibits RIG-I/MDA5 activation complex, M protein interferes with TANK, IKKε, and TBK1 signaling, and PLpro inhibits various RIG-I, MDA5, and MAVs downstream signaling steps.
T83 9613-9716 Sentence denotes SARS-CoV-2 proteins acting at various steps in blocking NAS and IFN signaling are shown in the red box.
T84 9717-10287 Sentence denotes NAS, Nucleic acid sensors; RIG-I, Retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; TRAF, TNF receptor-associated factor; STING, ER-associated stimulator of interferon genes; FADD, FAS-associated death domain protein; IRF, Interferon regulatory factor (IRF3/7); TRADD, TNFR1-associated death domain protein; IKKε, IκB kinase-ε; RIPK1, Receptor-interacting protein 1; TANK, TRAF family member-associated NF-kappa-B activator; TBK1, TANK-binding kinase 1; ISG, Interferon stimulatory gene; TRIM25, Tripartite motif-containing protein 25.
T85 10288-10498 Sentence denotes The role of these molecular sensors is not yet comprehensively studied in SARS-CoV-2, but a few recent reports suggest that these sensors are similarly involved in the early antiviral response during infection.
T86 10499-10704 Sentence denotes The immunoinformatic approach revealed the presence of a wide range of ssRNA SARS-CoV-2 genome fragments as potential molecular PAMPs which were presumed to mediate signaling via endogenous TLR7/8 pathway.
T87 10705-10942 Sentence denotes Further, it is appearing that the number of PAMPs (genomic fragments) was higher in the SARS-CoV-2 genome as compared to SARS-CoV, suggesting that SARS-CoV-2 may drive relatively more robust immune response (Moreno-Eutimio et al., 2020).
T88 10943-11180 Sentence denotes Single-cell RNA-sequencing (scRNA-seq) study in PBMCs derived from ICU patients revealed extensive upregulation of NAS pathway genes including RIG-I, MDA5, and LGP2, suggesting an invasion of SARS-CoV-2 in these cells (Wei et al., 2020).
T89 11181-11282 Sentence denotes However, no direct assays were performed in these cells to find the presence or absence of viral RNA.
T90 11283-11531 Sentence denotes These findings may imply that that the SARS-CoV-2, does not directly infect PBMCs and thus this upregulation of NAS genes may be through passive uptake of the virus, most probably by antibody-dependent enhancement (ADE), as will be discussed later.
T91 11532-11640 Sentence denotes Similarly, endogenous TLR7 and TLR8 upregulate along with an increase in expression of MAVS, IRF3, and IRF7.
T92 11641-11880 Sentence denotes The functional importance of this upregulated expression of NAS pathway genes remains unclear and hence more research in this direction will clarify the specific role of these molecular sensors in the antiviral response against SARS-CoV-2.