| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T64 |
0-27 |
Sentence |
denotes |
Viral Entry and Replication |
| T65 |
28-125 |
Sentence |
denotes |
A virus starts its infection by binding viral particles to the host’s surface cellular receptors. |
| T66 |
126-260 |
Sentence |
denotes |
The recognition of cellular receptors is the first step towards viral entry into host cells, in addition to determining their tropism. |
| T67 |
261-479 |
Sentence |
denotes |
The ability to engage receptors and the affinity of binding can define the efficiency of a virus when infecting an organism, while the amount of these receptors present in cells can indicate the intensity of infection. |
| T68 |
480-697 |
Sentence |
denotes |
Viruses that have a high capacity to bind to more conserved receptors are more likely to migrate between different species, which may also reflect the susceptibility of hosts and increase viral pathogenicity (40, 41). |
| T69 |
698-858 |
Sentence |
denotes |
As well as the other β-CoVs, the SARS-CoV-2 genome has a long open reading frame (ORF) 1ab region, followed by regions that encode S, E, M, and N proteins (42). |
| T70 |
859-975 |
Sentence |
denotes |
Homotrimers of S proteins are present on the viral surface and are responsible for attaching to host receptors (43). |
| T71 |
976-1102 |
Sentence |
denotes |
The E protein plays a role in the assembly and release of the virus, in addition to being involved in viral pathogenesis (44). |
| T72 |
1103-1241 |
Sentence |
denotes |
The M protein has three transmembrane domains and shapes the virions, promotes membrane curvature, and binds to the nucleocapsid (45, 46). |
| T73 |
1242-1467 |
Sentence |
denotes |
Lastly, the N protein contains two domains that can bind to the RNA virus and is also an antagonist of interferon (IFN) and a virally-encoded repressor of RNA interference, which appears to benefit viral replication (47, 48). |
| T74 |
1468-1626 |
Sentence |
denotes |
The S protein of SARS-CoV-2 plays an important role in determining tropism for being able to activate receptors in host cells and induce the invasion process. |
| T75 |
1627-1779 |
Sentence |
denotes |
This protein is cleaved by proteases into the S1 and S2 subunits, which are responsible for receptor recognition and membrane fusion, respectively (39). |
| T76 |
1780-2138 |
Sentence |
denotes |
Several articles have experimentally demonstrated that the RDB in the S protein, especially in the S1 region, binds to the peptidase domain (PD) of the ACE2 receptor, which is part of the renin-angiotensin-aldosterone system, an enzyme present in the plasma membrane mainly of pulmonary, endothelial, cardiac, renal, and intestinal cells (7, 22, 38, 49, 50). |
| T77 |
2139-2292 |
Sentence |
denotes |
The S2 subunit is known to contain the fusion peptide, in which it is inserted into the host cell membrane to trigger the fusogenic reaction (7, 51, 52). |
| T78 |
2293-2431 |
Sentence |
denotes |
The interaction of the S glycoprotein with the CD26 receptor and CD209L (39, 53, 54) is also suggested, however, its role remains unclear. |
| T79 |
2432-2677 |
Sentence |
denotes |
The binding of the virus to the ACE2 receptor causes stabilization of the RBD in the standing-up state and triggers conformational changes in the S complex, resulting in the release of the S1 subunit and activation of S2 fusogenic activity (55). |
| T80 |
2678-2840 |
Sentence |
denotes |
The S2 subunit contains an N-terminal fusion peptide (FP), heptad repeat 1 (HR1), heptad repeat 2 (HR2), a transmembrane region (TM), and a cytoplasmic tail (CT). |
| T81 |
2841-3113 |
Sentence |
denotes |
During the fusion process, the FP portion is exposed and inserts into the membrane of the target cell, leading to a modification in S2, then the HR1 and HR2 come together to form a six-helical bundle (6-HR) structure, which allows the fusion between the membranes (55–57). |
| T82 |
3114-3255 |
Sentence |
denotes |
Therefore, CoVs need to elicit exogenous proteases to perform modifications of their binding receptors necessary for the connection to occur. |
| T83 |
3256-3484 |
Sentence |
denotes |
SARS-CoV-2 has its own furin-like proteases, which play a role in these changes, providing it with an evolutionary advantage in relation to other coronaviruses and improving the process of cell infection and viral dissemination. |
| T84 |
3485-3610 |
Sentence |
denotes |
Concerning exogenous proteins, SARS-CoV-2 can also use host proteins to prepare its S glycoprotein for receptor binding (49). |
| T85 |
3611-3825 |
Sentence |
denotes |
Hoffman et al. (7) demonstrated in vitro that strains of the virus isolated from COVID-19 patients can use both the host protease transmembrane serine protease 2 (TMPRSS2) and cathepsins B/L to prime the S protein. |
| T86 |
3826-4025 |
Sentence |
denotes |
The entry mechanism of CoVs in host cells depends on the strain and species considered, as well as tissue and cell-type specificities (receptor/protease availability and local microenvironment) (58). |
| T87 |
4026-4220 |
Sentence |
denotes |
After binding to a target host cell via interactions with cellular receptors, viral entry of CoVs can occur in two manners: (i) the endosomal pathway and (ii) the non-endosomal pathway (59, 60). |
| T88 |
4221-4455 |
Sentence |
denotes |
The endosomal pathway is facilitated by low pH and pH-dependent endosomal cysteine protease cathepsins, helping to overcome the energetically unfavorable membrane fusion reaction and facilitating endosomal cell entry of CoVs (61, 62). |
| T89 |
4456-4573 |
Sentence |
denotes |
The non-endosomal pathway is dependent on TMPRSS2, which allows the activation of the S protein for viral entry (63). |
| T90 |
4574-4843 |
Sentence |
denotes |
Once the viral genome is inside the host cell cytoplasm, translation of viral RNA produces RNA-dependent RNA polymerase (RdRp), which uses viral RNA as a template to generate virus-specific mRNAs (subgenomic mRNAs) from subgenomic negative-strand intermediates (64–66). |
| T91 |
4844-4947 |
Sentence |
denotes |
Translation of subgenomic mRNAs leads to the production of structural and nonstructural viral proteins. |
| T92 |
4948-5159 |
Sentence |
denotes |
Thus, after their formation, structural proteins are inserted into the membrane of the endoplasmic reticulum or Golgi, and viral particles germinate into the endoplasmic reticulum-Golgi intermediate compartment. |
| T93 |
5160-5277 |
Sentence |
denotes |
Finally, the vesicles containing the virus particles fuse with the plasma membrane to release the virus (65, 67, 68). |
| T94 |
5278-5348 |
Sentence |
denotes |
Another possible mechanism for CoV entry may occur through antibodies. |
| T95 |
5349-5711 |
Sentence |
denotes |
During the binding of the virus-antibody complex, simultaneous binding of viral proteins to antigen-binding fragment (Fab) regions of immunoglobulin G (IgG) and of the fragment crystallizable (Fc) portion of the antibody to Fc gamma receptors (FcγRs) that are expressed by immune cells occurs, promoting viral entry without the use of the ACE2 receptor (69, 70). |
| T96 |
5712-5989 |
Sentence |
denotes |
However, the presence of viral RNA in the endosomes signals via the Toll-like 3 (TLR3), TLR7, or TLR8 receptor, activating the host cell to release pro-inflammatory cytokines that lead to exacerbated tissue damage, a phenomenon called antibody-dependent enhancement (ADE) (71). |
| T97 |
5990-6271 |
Sentence |
denotes |
Such a mechanism for SARS‐CoV‐2 is not yet fully understood, but previous coronavirus infections or SARS‐CoV‐2 convalescent patients with different SARS‐CoV‐2 strains could promote ADE, as experimentally shown for antibodies against the MERS‐CoV or SARS‐CoV-1 spike S protein (72). |
| T98 |
6272-6495 |
Sentence |
denotes |
Several studies have shown that sera administration induced increased SARS-CoV-1 viral entry into cells that express the Fc receptor, and serum-dependent SARS-CoV-1 entry does not pass through the endosome pathway (73, 74). |
| T99 |
6496-6777 |
Sentence |
denotes |
This mechanism was characterized by Yip et al. (75) and Wang et al. (76), who revealed that the anti-Spike protein antibodies were in fact responsible for the infection of immune cells, and the enhancement of the infection can be improved by increasing the dilutions of antibodies. |
| T100 |
6778-7018 |
Sentence |
denotes |
In relation to MERS-CoV, a similar mechanism has been demonstrated, since neutralizing monoclonal antibodies (nAb) are able to bind to the spike-S surface protein, allowing conformational changes and being subject to proteolytic activation. |
| T101 |
7019-7161 |
Sentence |
denotes |
Meanwhile, nAb binds to the cell surface IgG Fc receptor, guiding viral entry through canonical pathways dependent on the viral receptor (77). |
| T102 |
7162-7443 |
Sentence |
denotes |
Recent studies with COVID-19 patients reported that there was a strong IgG antibody response against the nucleocapsid protein and a delay in eliminating the virus, leading to an increase in the severity of the infection and contributing to the hypothesis of ADE of SARS-CoV-2 (78). |
| T103 |
7444-7687 |
Sentence |
denotes |
In view of this, the geographic discrepancy in pathogenesis can be explained, since individuals who have experienced previous exposure to coronaviruses are experiencing the effects of ADE due to the heterogeneity of the antigenic epitope (79). |
| T104 |
7688-7866 |
Sentence |
denotes |
In addition, the potential of human antibodies for vaccination will depend on whether antibodies play a role in disease progression or in protecting against viral infection (70). |
| T105 |
7867-8127 |
Sentence |
denotes |
As an evasion mechanism, CoVs use a glycan conformational shield to prevent the recognition of the virus by the immune system, and, for this reason, S glycoproteins are found in trimers form and require structural alterations to engage with cellular receptors. |
| T106 |
8128-8366 |
Sentence |
denotes |
In most of the hCoVs described, these S trimers are found in a naturally closed conformation, however, this mechanism also causes a delay in the process of cell infection due to the need for major changes in the glycoprotein conformation. |
| T107 |
8367-8627 |
Sentence |
denotes |
It was described that, in SARS-CoV-2, the S trimers seem to exist in a partially open state, which prevents recognition by the immune system, but accelerates the initiation of conformational changes in the receptor and the processes of binding and fusion (49). |
