| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T31 |
0-56 |
Sentence |
denotes |
Innate Nucleic Acid Sensing and Viral Evasion Mechanisms |
| T32 |
58-101 |
Sentence |
denotes |
Nucleic Acid Sensors in Antiviral Signaling |
| T33 |
102-257 |
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 |
258-585 |
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 |
586-863 |
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 |
864-1282 |
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 |
1283-1377 |
Sentence |
denotes |
All these cell types express the S protein target receptor ACE2, albeit with lower expression. |
| T38 |
1378-1525 |
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 |
1526-1591 |
Sentence |
denotes |
FIGURE 1 Proposed model of SARS-CoV-2 entry into the host cells. |
| T40 |
1592-1845 |
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 |
1846-2089 |
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 |
2090-2672 |
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 |
2673-2802 |
Sentence |
denotes |
During subsequent infection cycles, the virus may utilize either cell membrane or (8–11) the more probable endocytic entry route. |
| T44 |
2803-3165 |
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 |
3166-3388 |
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 |
3389-3537 |
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 |
3538-3636 |
Sentence |
denotes |
These inhibitory signals affect a range of host defense pathways to allow the propagation of CoVs. |
| T48 |
3637-3739 |
Sentence |
denotes |
Some inhibitory signals may even activate cell death pathway to induce a robust proinflammatory state. |
| T49 |
3740-4067 |
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 |
4068-4275 |
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 |
4276-4440 |
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 |
4441-4623 |
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 |
4624-4828 |
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 |
4829-5082 |
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 |
5083-5188 |
Sentence |
denotes |
RIG-I binds to 5’-PPP RNA and short dsRNA, while MDA5 binds to longer RNA fragments (Huang et al., 2014). |
| T56 |
5189-5338 |
Sentence |
denotes |
Binding of pathogenic RNAs induces conformational changes in RIG-I and MDA5, and after that post-translational modifications activate these proteins. |
| T57 |
5339-5697 |
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 |
5698-5789 |
Sentence |
denotes |
LGP2 acts as a facilitator to enhance viral sensing by RIG-1 and MDA5 (Satoh et al., 2010). |
| T59 |
5790-6025 |
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 |
6026-6206 |
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 |
6207-6428 |
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 |
6429-6612 |
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 |
6613-6830 |
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 |
6831-6976 |
Sentence |
denotes |
In animal studies, mice that are deficient in TLR signaling exhibit robust infection and severe pathological condition during SARS-CoV infection. |
| T65 |
6977-7116 |
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 |
7117-7326 |
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 |
7327-7613 |
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 |
7614-7762 |
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 |
7763-7977 |
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 |
7978-8098 |
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 |
8099-8241 |
Sentence |
denotes |
However, if successfully recognized, RIG-I and MDA5 get activated and subsequently activate the centrally placed MAVS located on mitochondria. |
| T72 |
8242-8309 |
Sentence |
denotes |
MAVS acts as a molecular adaptor that further recruits TRAF2/3/5/6. |
| T73 |
8310-8438 |
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 |
8439-8532 |
Sentence |
denotes |
At the MAVS junction, the association of TRAF5/6 with TRADD, FADD, and RIPK1 activates NF-κB. |
| T75 |
8533-8702 |
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 |
8703-8994 |
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 |
8995-9104 |
Sentence |
denotes |
Signaling via IFNRs activates the JAK/STAT signaling pathway and subsequently induces the expression of ISGs. |
| T78 |
9105-9178 |
Sentence |
denotes |
These molecular events were recently reviewed (Rehwinkel and Gack, 2020). |
| T79 |
9179-9238 |
Sentence |
denotes |
ISGs transcribed will eventually inhibit viral propagation. |
| T80 |
9239-9380 |
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 |
9381-9443 |
Sentence |
denotes |
NSP4a inhibits TRIM25, which is required for RIG-I activation. |
| T82 |
9444-9670 |
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 |
9671-9774 |
Sentence |
denotes |
SARS-CoV-2 proteins acting at various steps in blocking NAS and IFN signaling are shown in the red box. |
| T84 |
9775-10345 |
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 |
10346-10556 |
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 |
10557-10762 |
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 |
10763-11000 |
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 |
11001-11238 |
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 |
11239-11340 |
Sentence |
denotes |
However, no direct assays were performed in these cells to find the presence or absence of viral RNA. |
| T90 |
11341-11589 |
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 |
11590-11698 |
Sentence |
denotes |
Similarly, endogenous TLR7 and TLR8 upregulate along with an increase in expression of MAVS, IRF3, and IRF7. |
| T92 |
11699-11938 |
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. |
| T93 |
11940-11980 |
Sentence |
denotes |
Evasions Mechanism Employed by SARS-CoVs |
| T94 |
11981-12092 |
Sentence |
denotes |
All human infecting SARS-CoVs are known to have evolved multiple mechanisms to evade recognition by host cells. |
| T95 |
12093-12221 |
Sentence |
denotes |
Emerging evidence suggests that similar mechanisms are employed by SARS-CoV-2 to inhibit or delay the host cell immune response. |
| T96 |
12222-12271 |
Sentence |
denotes |
Some of these mechanisms will be discussed below. |
| T97 |
12273-12340 |
Sentence |
denotes |
Interference With the Nucleic Acid Sensing and Downstream Signaling |
| T98 |
12341-12529 |
Sentence |
denotes |
Previous studies on SARS-CoV revealed smart strategies to inhibit multiple steps in the NAS pathway and downstream signaling (Rose et al., 2010; Adedeji et al., 2013; Chan and Gack, 2016). |
| T99 |
12530-12599 |
Sentence |
denotes |
As mentioned earlier, TRIM25 mediated ubiquitination activates RIG-I. |
| T100 |
12600-12727 |
Sentence |
denotes |
Whereas, the N protein of SARS-CoV, which binds to TRIM25 and thereby prevents its association with RIG-I and hence activation. |
| T101 |
12728-12852 |
Sentence |
denotes |
The ubiquitin usurped RIG-I is unable to mount the antiviral response, thereby disabling IFN-β production (Hu et al., 2017). |
| T102 |
12853-13068 |
Sentence |
denotes |
N protein also antagonizes IFN signaling by directly interacting with IRF3, thereby inhibiting its phosphorylation and subsequent nuclear translocation (Kopecky-Bromberg et al., 2006; Kopecky-Bromberg et al., 2007). |
| T103 |
13069-13216 |
Sentence |
denotes |
Similarly, M protein inhibits IRF3/IRF7 signaling by interfering with RIG-I, TBK1, IKKε, and TRAF3 activation complex formation (Siu et al., 2009). |
| T104 |
13217-13445 |
Sentence |
denotes |
Acting at multiple pathways on host cells, Nsp1 inhibits IFN-β promoter activity and STAT1 phosphorylation which led to a decrease in the expression of various antiviral interferon-stimulated genes (ISGs; Wathelet et al., 2007). |
| T105 |
13446-13616 |
Sentence |
denotes |
Chen et al. (2014) showed that papain-like protease (PLpro) directly associates with TRAF3, TBK1, IKKε, STING, and IRF3 and hence inhibits downstream IRF3/IRF7 signaling. |
| T106 |
13617-13746 |
Sentence |
denotes |
In another study, Devaraj et al. (2007) showed that PLpro inhibits IRF3 phosphorylation and its subsequent nuclear translocation. |
| T107 |
13747-13952 |
Sentence |
denotes |
ORF3b, ORF6, ORF8a, and ORF8b also play prominent roles in inhibiting IRF3 phosphorylation and its subsequent nuclear translocation (Kopecky-Bromberg et al., 2006; Freundt et al., 2010; Wong et al., 2018). |
| T108 |
13953-14142 |
Sentence |
denotes |
ORF9b was shown to be associated with mitochondria and induced degradation of dynamin-related protein 1 (Drp1), thus altering mitochondrial function and sequestering MAVS into small puncta. |
| T109 |
14143-14356 |
Sentence |
denotes |
Further, ORF9b was associated with recruitment of ubiquitin ligases PCBP2 and AIP4 E3 which led to ubiquitination of MAVS and eventually its degradation, as a result inhibiting IFN-β production (Shi et al., 2014). |
| T110 |
14357-14511 |
Sentence |
denotes |
Thus, by associating with multiple proteins involved in NAS signaling, SARS-CoV antagonizes IFN signaling and synthesis of protective molecules like ISGs. |
| T111 |
14512-14666 |
Sentence |
denotes |
Recent studies have also demonstrated the interaction of SARS-CoV-2 proteins with multiple host cell NAS signaling molecules and downstream IFN signaling. |
| T112 |
14667-14791 |
Sentence |
denotes |
An extensive proteomic study by Gordon et al. (2020), showed multiple SARS-CoV-2 protein and host cell protein interactions. |
| T113 |
14792-14890 |
Sentence |
denotes |
A proteome map of 26 SARS-CoV-2 proteins predicted 332 viral proteins interacting with host cells. |
| T114 |
14891-15034 |
Sentence |
denotes |
Among these, Nsp9, Nsp13, Nsp15, ORF3a, ORF9b, and ORF9c interacted with proteins in downstream NAS signaling, IFN response, and NF-κB pathway. |
| T115 |
15035-15250 |
Sentence |
denotes |
Similarly, Nsp5 interacted with HDAC2, which may be thus involved in limiting the IFN signaling and inflammatory response, but the specific functional role of these proteins was not determined (Gordon et al., 2020). |
| T116 |
15251-15345 |
Sentence |
denotes |
In two recent studies, the functional relevance of some of these proteins was tested in vitro. |
| T117 |
15346-15536 |
Sentence |
denotes |
In the first study, Li J.Y. et al. (2020) tested the effects of ORF6, ORF8 and N protein on the antiviral response in HEK293 cells and found these proteins inhibit IFN-β and NF-κB signaling. |
| T118 |
15537-15704 |
Sentence |
denotes |
Similarly, Yuen et al. (2020) showed that IFN antagonizing effect of ORF6 was due to its association with the interferon-inducible nuclear export complex (NUP98–RAE1). |
| T119 |
15705-15850 |
Sentence |
denotes |
The study further showed that Nsp13, Nsp14, and Nsp15 could also antagonize IFN response, but the mechanism was not explored (Yuen et al., 2020). |
| T120 |
15851-15983 |
Sentence |
denotes |
In addition to interfering with IFN production pathway, SARS-CoV has evolved multiple other mechanisms to modify host cell response. |
| T121 |
15984-16133 |
Sentence |
denotes |
Viral RNA is unprotected and open to cellular degradation; however, some RNA viruses have evolved a capping process to evade recognition by the host. |
| T122 |
16134-16286 |
Sentence |
denotes |
In SARS-CoV, Nsp16 provides ribose 2′-O-methylation at the 5′ end of the RNA to protect its degradation and prevent sensing by MDA5 (Züst et al., 2011). |
| T123 |
16287-16395 |
Sentence |
denotes |
Similarly, Nsp14 had N7 methyltransferase activity and methylated the 5′ end of the RNA (Chen et al., 2009). |
| T124 |
16396-16555 |
Sentence |
denotes |
Other SARS-CoV proteins involved include – Nsp4a, which prevents stress granule formation by inhibiting PKR mediated antiviral signaling (Rabouw et al., 2016). |
| T125 |
16556-16686 |
Sentence |
denotes |
N protein of SARS-CoV-2 is also known to interact with the proteins implicated in stress granule regulation (Gordon et al., 2020). |
| T126 |
16687-16920 |
Sentence |
denotes |
Electron tomography studies in SARS-CoV infected cells revealed a unique replication network derived from ER to organize viral replication while simultaneously hiding the viral RNA from recognition by host NASs (Knoops et al., 2008). |
| T127 |
16921-17127 |
Sentence |
denotes |
Other RNA viruses have also developed similar strategies to evade sensing by forming double-membrane vesicles (DMVs) and replication organelles to prevent access to the NASs (Blanchard and Roingeard, 2015). |
| T128 |
17129-17203 |
Sentence |
denotes |
Inhibition of Host Cell Biosynthetic Pathways and Modulation of Cell Death |
| T129 |
17204-17308 |
Sentence |
denotes |
Both SARS-CoV and SARS-CoV-2 have evolved multiple inhibitory mechanisms to evade host cell recognition. |
| T130 |
17309-17468 |
Sentence |
denotes |
Inhibition of host transcriptional and translational machinery prevents the biosynthesis of protective IFNs and delays early activation of host cell apoptosis. |
| T131 |
17469-17573 |
Sentence |
denotes |
Nsp1 of SARS-CoV inhibit the loading of ribosomal 40s subunit and prevent host cell protein translation. |
| T132 |
17574-17718 |
Sentence |
denotes |
Further, Nsp1 specifically degrade host cell RNA while sparing the viral RNA (Huang et al., 2011; Tanaka et al., 2012; Lokugamage et al., 2015). |
| T133 |
17719-17822 |
Sentence |
denotes |
N protein of SARS-CoV-2 also interacts with the host biosynthetic protein La-related protein 1 (LARP1). |
| T134 |
17823-17975 |
Sentence |
denotes |
This interaction may serve as the necessary signal to shut down the host cell protein synthesis for the propagation of SARS-CoV-2 (Gordon et al., 2020). |
| T135 |
17976-18198 |
Sentence |
denotes |
Papain-like protease of SARS-CoV directly interacts with p53 and induce its degradation, which may thus interfere with translation and delay early apoptosis of the infected cells (Yuan et al., 2015; Ma-Lauer et al., 2016). |
| T136 |
18199-18365 |
Sentence |
denotes |
SARS-CoV S protein also interacts with the translation initiation factor eIF3f and inhibit host cell translation by preventing its nuclear import (Xiao et al., 2008). |
| T137 |
18366-18605 |
Sentence |
denotes |
Studies from other respiratory viruses have shown that cells which activate early apoptosis prevent further spread of the viruses, whereas viruses that successfully inhibit this pathway exhibit strong infectivity (Orzalli and Kagan, 2017). |
| T138 |
18606-18797 |
Sentence |
denotes |
Cytomegaloviruses (CMVs) distinctly rely on this mechanism to successfully replicate within the host cell by inhibiting apoptosis-modulatory proteins such as Bax and Bcl-2 (Çam et al., 2010). |
| T139 |
18798-19024 |
Sentence |
denotes |
However, whether SARS-CoV or SARS-CoV-2 are also directly involved in inhibiting early apoptosis remains to be tested, but it is evident that these viruses induce host cell death after successful propagation and dissemination. |
| T140 |
19025-19151 |
Sentence |
denotes |
SARS-CoV Nsp7a was shown to interact with prosurvival protein Bcl-X and induce apoptosis in cells in vitro (Tan et al., 2007). |
| T141 |
19152-19285 |
Sentence |
denotes |
Similarly, ORF3a leads to fragmentation of the Golgi apparatus, and induction of apoptosis (Waye et al., 2005; Freundt et al., 2010). |
| T142 |
19286-19434 |
Sentence |
denotes |
Besides this, ORF3a also implicates necroptotic cell death by interacting with and activating the main necroptosis protein RIPK3 (Yue et al., 2018). |
| T143 |
19435-19535 |
Sentence |
denotes |
Owing to its role in cell death pathways, the ORF3a of SARS-CoV-2 was also explored in this context. |
| T144 |
19536-19658 |
Sentence |
denotes |
This protein similarly induced apoptosis in HEK293 cells by activating the caspase 8-dependent pathway (Ren et al., 2020). |
| T145 |
19659-19892 |
Sentence |
denotes |
Interestingly, the results, that ORF3a of SARS-CoV-2 induces relatively lower apoptosis in several cell lines as compared to SARS-CoV, suggesting that this mechanism could provide an early advantage for the propagation of SARS-CoV-2. |
| T146 |
19893-20113 |
Sentence |
denotes |
Further, the proteome map of SARS-CoV-2 predicted interaction of Nsp12 with RIPK1, suggesting that this viral protein may also implicate in regulating host cell apoptotic and necroptotic cell death (Gordon et al., 2020). |
| T147 |
20114-20383 |
Sentence |
denotes |
However, a study on 25 cell lines in culture showed SARS-CoV-2 exhibiting cytopathic effect on only two cells, indicating that the differences could exist between these two related viruses in their property to interfere with host cell death pathways (Chu et al., 2020). |
| T148 |
20384-20573 |
Sentence |
denotes |
Thus, more comprehensive studies are needed to provide better molecular insights by which SARS-CoV-2 modulates host cell death pathways, which may also open new opportunities for treatment. |
| T149 |
20574-20842 |
Sentence |
denotes |
Based on these early observations, it is becoming evident that SARS-CoV-2 interferes with host NAS, IFN, biosynthetic, and cell death pathways to prevent early immune response and thus contribute to the underlying immunopathogenesis, as will be discussed subsequently. |
| T150 |
20843-21040 |
Sentence |
denotes |
To make these details simple, here we compiled the role of various SARS-CoV and SARS-CoV-2 proteins and their host cell interacting proteins and presented in the Table form (Supplementary Table 1). |
