Dataset Information

SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19.

ABSTRACT:

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.

SUBMITTER: Sahanic S

PROVIDER: S-EPMC10686889 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19.

Sahanic Sabina S Hilbe Richard R Dünser Christina C Tymoszuk Piotr P Löffler-Ragg Judith J Rieder Dietmar D Trajanoski Zlatko Z Krogsdam Anne A Demetz Egon E Yurchenko Maria M Fischer Christine C Schirmer Michael M Theurl Markus M Lener Daniela D Hirsch Jakob J Holfeld Johannes J Gollmann-Tepeköylü Can C Zinner Carl P CP Tzankov Alexandar A Zhang Shen-Ying SY Casanova Jean-Laurent JL Posch Wilfried W Wilflingseder Doris D Weiss Guenter G Tancevski Ivan I

Heliyon 20231117 11

<h4>Background</h4>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).<h4>Objective</h4>We investigated the engagement of SARS-CoV-2 with TLR4 in order to better understand how to tackle hyperinflammation in COVID-19.<h4>Methods</h4>We combined RNA-sequencing data of ...[more]

PMID: 38034686

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Dataset Information

SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19.

Background

Objective

Methods

Results

Conclusion

Take-home message

Publications

SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19.

Similar Datasets

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