tetano
Editor, Senior Moderator
Heliyon
. 2023 Nov 17;9(11):e21893.
doi: 10.1016/j.heliyon.2023.e21893. eCollection 2023 Nov. SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19
Sabina Sahanic[SUP] 1 [/SUP], Richard Hilbe[SUP] 1 [/SUP], Christina Dünser[SUP] 1 [/SUP], Piotr Tymoszuk[SUP] 1 [/SUP], Judith Löffler-Ragg[SUP] 1 [/SUP], Dietmar Rieder[SUP] 2 [/SUP], Zlatko Trajanoski[SUP] 2 [/SUP], Anne Krogsdam[SUP] 2 [/SUP], Egon Demetz[SUP] 1 [/SUP], Maria Yurchenko[SUP] 3 4 [/SUP], Christine Fischer[SUP] 1 [/SUP], Michael Schirmer[SUP] 1 [/SUP], Markus Theurl[SUP] 5 [/SUP], Daniela Lener[SUP] 5 [/SUP], Jakob Hirsch[SUP] 6 [/SUP], Johannes Holfeld[SUP] 6 [/SUP], Can Gollmann-Tepeköylü[SUP] 6 [/SUP], Carl P Zinner[SUP] 7 [/SUP], Alexandar Tzankov[SUP] 7 [/SUP], Shen-Ying Zhang[SUP] 8 9 10 [/SUP], Jean-Laurent Casanova[SUP] 8 9 10 11 [/SUP], Wilfried Posch[SUP] 12 [/SUP], Doris Wilflingseder[SUP] 12 [/SUP], Guenter Weiss[SUP] 1 [/SUP], Ivan Tancevski[SUP] 1 [/SUP]
Affiliations
Background: Toll-like receptors (TLRs) play a pivotal role in the immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exaggerated inflammatory response of innate immune cells, however, may drive morbidity and death in Coronavirus disease 19 (COVID-19).
Objective: We investigated the engagement of SARS-CoV-2 with TLR4 in order to better understand how to tackle hyperinflammation in COVID-19.
Methods: We combined RNA-sequencing data of human lung tissue and of bronchoalveolar lavage fluid cells derived from COVID-19 patients with functional studies in human macrophages using SARS-CoV-2 spike proteins and viable SARS-CoV-2. Pharmacological inhibitors as well as gene editing with CRISPR/Cas9 were used to delineate the signalling pathways involved.
Results: We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron).
Conclusion: Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19.
Take-home message: Our study combining human lung transcriptomics with functional studies in human macrophages clearly supports the design and development of TLR4 - directed therapeutics to mitigate hyperinflammation in severe COVID-19.
Keywords: COVID-19; Innate immunity; Macrophages; SARS-CoV-2; Toll-like receptors.
. 2023 Nov 17;9(11):e21893.
doi: 10.1016/j.heliyon.2023.e21893. eCollection 2023 Nov. SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19
Sabina Sahanic[SUP] 1 [/SUP], Richard Hilbe[SUP] 1 [/SUP], Christina Dünser[SUP] 1 [/SUP], Piotr Tymoszuk[SUP] 1 [/SUP], Judith Löffler-Ragg[SUP] 1 [/SUP], Dietmar Rieder[SUP] 2 [/SUP], Zlatko Trajanoski[SUP] 2 [/SUP], Anne Krogsdam[SUP] 2 [/SUP], Egon Demetz[SUP] 1 [/SUP], Maria Yurchenko[SUP] 3 4 [/SUP], Christine Fischer[SUP] 1 [/SUP], Michael Schirmer[SUP] 1 [/SUP], Markus Theurl[SUP] 5 [/SUP], Daniela Lener[SUP] 5 [/SUP], Jakob Hirsch[SUP] 6 [/SUP], Johannes Holfeld[SUP] 6 [/SUP], Can Gollmann-Tepeköylü[SUP] 6 [/SUP], Carl P Zinner[SUP] 7 [/SUP], Alexandar Tzankov[SUP] 7 [/SUP], Shen-Ying Zhang[SUP] 8 9 10 [/SUP], Jean-Laurent Casanova[SUP] 8 9 10 11 [/SUP], Wilfried Posch[SUP] 12 [/SUP], Doris Wilflingseder[SUP] 12 [/SUP], Guenter Weiss[SUP] 1 [/SUP], Ivan Tancevski[SUP] 1 [/SUP]
Affiliations
- PMID: 38034686
- PMCID: PMC10686889
- DOI: 10.1016/j.heliyon.2023.e21893
Background: Toll-like receptors (TLRs) play a pivotal role in the immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exaggerated inflammatory response of innate immune cells, however, may drive morbidity and death in Coronavirus disease 19 (COVID-19).
Objective: We investigated the engagement of SARS-CoV-2 with TLR4 in order to better understand how to tackle hyperinflammation in COVID-19.
Methods: We combined RNA-sequencing data of human lung tissue and of bronchoalveolar lavage fluid cells derived from COVID-19 patients with functional studies in human macrophages using SARS-CoV-2 spike proteins and viable SARS-CoV-2. Pharmacological inhibitors as well as gene editing with CRISPR/Cas9 were used to delineate the signalling pathways involved.
Results: We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron).
Conclusion: Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19.
Take-home message: Our study combining human lung transcriptomics with functional studies in human macrophages clearly supports the design and development of TLR4 - directed therapeutics to mitigate hyperinflammation in severe COVID-19.
Keywords: COVID-19; Innate immunity; Macrophages; SARS-CoV-2; Toll-like receptors.