PMC:7546716 / 17734-20855 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7546716","sourcedb":"PMC","sourceid":"7546716","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7546716","text":"Suppression of antiviral responses and hyperinflammation\nAdvanced 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. 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. 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\nAn 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\nHigh 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 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