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C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia

BACKGROUND: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality. OBJECTIVE: Complement hyperactivation promotes lung injury and was ob...

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Autores principales: Posch, Wilfried, Vosper, Jonathan, Noureen, Asma, Zaderer, Viktoria, Witting, Christina, Bertacchi, Giulia, Gstir, Ronald, Filipek, Przemyslaw A., Bonn, Günther K., Huber, Lukas A., Bellmann-Weiler, Rosa, Lass-Flörl, Cornelia, Wilflingseder, Doris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056780/
https://www.ncbi.nlm.nih.gov/pubmed/33852936
http://dx.doi.org/10.1016/j.jaci.2021.03.038
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author Posch, Wilfried
Vosper, Jonathan
Noureen, Asma
Zaderer, Viktoria
Witting, Christina
Bertacchi, Giulia
Gstir, Ronald
Filipek, Przemyslaw A.
Bonn, Günther K.
Huber, Lukas A.
Bellmann-Weiler, Rosa
Lass-Flörl, Cornelia
Wilflingseder, Doris
author_facet Posch, Wilfried
Vosper, Jonathan
Noureen, Asma
Zaderer, Viktoria
Witting, Christina
Bertacchi, Giulia
Gstir, Ronald
Filipek, Przemyslaw A.
Bonn, Günther K.
Huber, Lukas A.
Bellmann-Weiler, Rosa
Lass-Flörl, Cornelia
Wilflingseder, Doris
author_sort Posch, Wilfried
collection PubMed
description BACKGROUND: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality. OBJECTIVE: Complement hyperactivation promotes lung injury and was observed in patients suffering from Middle East respiratory syndrome-related coronavirus, SARS-CoV-1, and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells on exposure to SARS-CoV-2 in terms of complement component 3 (C3)-mediated effects. METHODS: For this, we used highly differentiated primary human 3-dimensional tissue models infected with SARS-CoV-2 patient isolates. On infection, viral load, viral infectivity, intracellular complement activation, inflammatory mechanisms, and tissue destruction were analyzed by real-time RT-PCR, high content screening, plaque assays, luminex analyses, and transepithelial electrical resistance measurements. RESULTS: Here, we show that primary normal human bronchial and small airway epithelial cells respond to SARS-CoV-2 infection by an inflated local C3 mobilization. SARS-CoV-2 infection resulted in exaggerated intracellular complement activation and destruction of the epithelial integrity in monolayer cultures of primary human airway cells and highly differentiated, pseudostratified, mucus-producing, ciliated respiratory tissue models. SARS-CoV-2–infected 3-dimensional cultures secreted significantly higher levels of C3a and the proinflammatory cytokines IL-6, monocyte chemoattractant protein 1, IL-1α, and RANTES. CONCLUSIONS: Crucially, we illustrate here for the first time that targeting the anaphylotoxin receptors C3a receptor and C5a receptor in nonimmune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19.
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spelling pubmed-80567802021-04-20 C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia Posch, Wilfried Vosper, Jonathan Noureen, Asma Zaderer, Viktoria Witting, Christina Bertacchi, Giulia Gstir, Ronald Filipek, Przemyslaw A. Bonn, Günther K. Huber, Lukas A. Bellmann-Weiler, Rosa Lass-Flörl, Cornelia Wilflingseder, Doris J Allergy Clin Immunol Covid-19 BACKGROUND: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality. OBJECTIVE: Complement hyperactivation promotes lung injury and was observed in patients suffering from Middle East respiratory syndrome-related coronavirus, SARS-CoV-1, and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells on exposure to SARS-CoV-2 in terms of complement component 3 (C3)-mediated effects. METHODS: For this, we used highly differentiated primary human 3-dimensional tissue models infected with SARS-CoV-2 patient isolates. On infection, viral load, viral infectivity, intracellular complement activation, inflammatory mechanisms, and tissue destruction were analyzed by real-time RT-PCR, high content screening, plaque assays, luminex analyses, and transepithelial electrical resistance measurements. RESULTS: Here, we show that primary normal human bronchial and small airway epithelial cells respond to SARS-CoV-2 infection by an inflated local C3 mobilization. SARS-CoV-2 infection resulted in exaggerated intracellular complement activation and destruction of the epithelial integrity in monolayer cultures of primary human airway cells and highly differentiated, pseudostratified, mucus-producing, ciliated respiratory tissue models. SARS-CoV-2–infected 3-dimensional cultures secreted significantly higher levels of C3a and the proinflammatory cytokines IL-6, monocyte chemoattractant protein 1, IL-1α, and RANTES. CONCLUSIONS: Crucially, we illustrate here for the first time that targeting the anaphylotoxin receptors C3a receptor and C5a receptor in nonimmune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19. The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. 2021-06 2021-04-20 /pmc/articles/PMC8056780/ /pubmed/33852936 http://dx.doi.org/10.1016/j.jaci.2021.03.038 Text en © 2021 The Authors Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Covid-19
Posch, Wilfried
Vosper, Jonathan
Noureen, Asma
Zaderer, Viktoria
Witting, Christina
Bertacchi, Giulia
Gstir, Ronald
Filipek, Przemyslaw A.
Bonn, Günther K.
Huber, Lukas A.
Bellmann-Weiler, Rosa
Lass-Flörl, Cornelia
Wilflingseder, Doris
C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia
title C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia
title_full C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia
title_fullStr C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia
title_full_unstemmed C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia
title_short C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia
title_sort c5ar inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in sars-cov-2–infected primary human airway epithelia
topic Covid-19
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056780/
https://www.ncbi.nlm.nih.gov/pubmed/33852936
http://dx.doi.org/10.1016/j.jaci.2021.03.038
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