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

Autor:	Sahanic S; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Hilbe R; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Dünser C; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Tymoszuk P; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Löffler-Ragg J; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Rieder D; Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Trajanoski Z; Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Krogsdam A; Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Demetz E; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Yurchenko M; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.; The Central Norway Regional Health Authority, St. Olavs Hospital HF, Trondheim, Norway., Fischer C; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Schirmer M; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Theurl M; Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria., Lener D; Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria., Hirsch J; Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria., Holfeld J; Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria., Gollmann-Tepeköylü C; Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria., Zinner CP; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland., Tzankov A; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland., Zhang SY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA., Casanova JL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.; Howard Hughes Medical Institute, New York, NY, 10065, USA., Posch W; Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Austria., Wilflingseder D; Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Austria., Weiss G; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria., Tancevski I; Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.
Jazyk:	angličtina
Zdroj:	Heliyon [Heliyon] 2023 Nov 17; Vol. 9 (11), pp. e21893. Date of Electronic Publication: 2023 Nov 17 (Print Publication: 2023).
DOI:	10.1016/j.heliyon.2023.e21893
Abstrakt:	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. Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. (© 2023 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu