tetano
Editor, Senior Moderator
Front Immunol
. 2023 Jan 13;13:1066456.
doi: 10.3389/fimmu.2022.1066456. eCollection 2022.
Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia
Thomas Wallach[SUP] 1 [/SUP], Martin Raden[SUP] 2 [/SUP], Lukas Hinkelmann[SUP] 1 [/SUP], Mariam Brehm[SUP] 1 [/SUP], Dominik Rabsch[SUP] 2 [/SUP], Hannah Weidling[SUP] 1 3 [/SUP], Christina Krüger[SUP] 1 [/SUP], Helmut Kettenmann[SUP] 3 [/SUP], Rolf Backofen[SUP] 2 4 [/SUP], Seija Lehnardt[SUP] 1 5 [/SUP]
Affiliations
Abstract
Introduction: The pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is marked by thromboembolic events and an inflammatory response throughout the body, including the brain.
Methods: Employing the machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate the viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells we tested such RNA fragments with respect to their potential to induce activation of human TLR7 and TLR8 and to activate human macrophages, as well as iPSC-derived human microglia, the resident immune cells in the brain.
Results: We experimentally validated several sequence-specific RNA fragment candidates out of the SARS-CoV-2 RNA fragments predicted in silico as activators of human TLR7 and TLR8. Moreover, these SARS-CoV-2 ssRNAs induced cytokine release from human macrophages and iPSC-derived human microglia in a sequence- and species-specific fashion.
Discussion: Our findings determine TLR7 and TLR8 as key sensors of SARS-CoV-2-derived ssRNAs and may deepen our understanding of the mechanisms how this virus triggers, but also modulates an inflammatory response through innate immune signaling.
Keywords: RNA; SARS-CoV-2; iPSC-derived human microglia; inflammatory response; macrophages; toll-like receptors.
. 2023 Jan 13;13:1066456.
doi: 10.3389/fimmu.2022.1066456. eCollection 2022.
Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia
Thomas Wallach[SUP] 1 [/SUP], Martin Raden[SUP] 2 [/SUP], Lukas Hinkelmann[SUP] 1 [/SUP], Mariam Brehm[SUP] 1 [/SUP], Dominik Rabsch[SUP] 2 [/SUP], Hannah Weidling[SUP] 1 3 [/SUP], Christina Krüger[SUP] 1 [/SUP], Helmut Kettenmann[SUP] 3 [/SUP], Rolf Backofen[SUP] 2 4 [/SUP], Seija Lehnardt[SUP] 1 5 [/SUP]
Affiliations
- PMID: 36713399
- PMCID: PMC9880480
- DOI: 10.3389/fimmu.2022.1066456
Abstract
Introduction: The pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is marked by thromboembolic events and an inflammatory response throughout the body, including the brain.
Methods: Employing the machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate the viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells we tested such RNA fragments with respect to their potential to induce activation of human TLR7 and TLR8 and to activate human macrophages, as well as iPSC-derived human microglia, the resident immune cells in the brain.
Results: We experimentally validated several sequence-specific RNA fragment candidates out of the SARS-CoV-2 RNA fragments predicted in silico as activators of human TLR7 and TLR8. Moreover, these SARS-CoV-2 ssRNAs induced cytokine release from human macrophages and iPSC-derived human microglia in a sequence- and species-specific fashion.
Discussion: Our findings determine TLR7 and TLR8 as key sensors of SARS-CoV-2-derived ssRNAs and may deepen our understanding of the mechanisms how this virus triggers, but also modulates an inflammatory response through innate immune signaling.
Keywords: RNA; SARS-CoV-2; iPSC-derived human microglia; inflammatory response; macrophages; toll-like receptors.