| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T75 |
0-56 |
Sentence |
denotes |
Suppression of antiviral responses and hyperinflammation |
| T76 |
57-435 |
Sentence |
denotes |
Advanced stages of COVID-19 are characterised by high circulating and pulmonary concentrations of IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA).6, 15, 25 The increased production of these molecules probably relates to high viral loads resulting in increased viroporins and subsequent activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome. |
| T77 |
436-820 |
Sentence |
denotes |
The strong expression of IL-1α, IL-1β, and IL-1RA is also due to monocyte activation and intense lung infiltration of monocyte-derived macrophages at later stages, as suggested by an abundance of CD14+IL-1β+ monocytes in the circulation of patients with COVID-19 in the early stages of recovery.46 Active IL-1β is produced following NLRP3 assembly and consequent caspase-1 activation. |
| T78 |
821-1051 |
Sentence |
denotes |
By modulating ion fluxes across host cell membranes, viroporins (in particular the ORF3a protein) have been shown to activate NLRP3 during SARS-CoV infection, and a similar mechanism might be at play during SARS-CoV-2 infection.47 |
| T79 |
1052-2360 |
Sentence |
denotes |
An imbalance in signalling from toll-like receptor (TLR) pathways, with the myeloid differentiation primary response protein (MyD88) pathway predominating over the TIR domain-containing adapter molecule 1 (TICAM-1, also known as TRIF) pathways, might further increase NLRP3 activation.48 Signalling downstream of IL-1 family receptors, including the IL-33 receptor ST2, and downstream of membrane TLRs, can activate MyD88 and elicit inflammation; whereas TRIF-mediated pathways downstream of endosomal TLRs would be expected to mount antiviral interferon responses and protect against coronaviruses.48, 49 Although coronaviruses are single-stranded RNA viruses that are predicted to bind directly to endosomal TLR7 and TLR8, and indirectly to TLR3 (using double-stranded RNA replication intermediates), aberrant inflammation induced by coronaviruses might instead involve membrane-expressed TLR2, as suggested by virus spike protein interactions with heparan sulphate-enriched regions of TLR2 in studies of the mouse hepatitis coronavirus.50 A predominance of MyD88 signalling over TRIF signalling would lead virus-exposed cells to produce high amounts of IL-1β, and NF-κB-induced cytokines and chemokines (eg, TNF, IL-8, IL-6, IL-12p40, IL-23, CCL2) rather than interferons, IL-12p35 and IL-12p70.30, 49, 50 |
| T80 |
2361-3121 |
Sentence |
denotes |
High concentrations of MyD88-related cytokines and reduced expression of TRIF-related cytokines characterise the cytokine milieu observed in the lungs of patients with severe and life-threatening COVID-19.15, 27, 28 Such an altered cytokine environment would polarise the immune response towards detrimental (Th17-sustained and GM-CSF-induced) hyperinflammation40, 41 caused by monocyte-derived macrophages and neutrophils, in place of protective (Th1-sustained and IFN-induced) antiviral responses exerted by cytotoxic T lymphocytes, natural killer cells, and B cells.29, 30 Altogether, coronaviruses seem to deceive and escape the immune system by eliciting a response that is generally more appropriate for extracellular rather than intracellular pathogens. |
