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C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2-infected primary human airway epithelia.
J Allergy Clin Immunol. 2021 06; 147(6):2083-2097.e6.JA

Abstract

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.

Links

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Authors+Show Affiliations

Posch W
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: wilfried.posch@i-med.ac.at.
Vosper J
Institute of Medical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
Noureen A
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Zaderer V
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Witting C
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Bertacchi G
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Gstir R
ADSI - Austrian Drug Screening Institute GmbH, Innsbruck, Austria.
Filipek PA
ADSI - Austrian Drug Screening Institute GmbH, Innsbruck, Austria.
Bonn GK
ADSI - Austrian Drug Screening Institute GmbH, Innsbruck, Austria.
Huber LA
ADSI - Austrian Drug Screening Institute GmbH, Innsbruck, Austria; Institute of Cell Biology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
Bellmann-Weiler R
University Hospital of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.
Lass-Flörl C
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Wilflingseder D
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: doris.wilflingseder@i-med.ac.at.

MeSH

BronchiCOVID-19Cell LineComplement ActivationComplement C3CytokinesEpithelial CellsHumansInflammationReceptor, Anaphylatoxin C5aRespiratory MucosaSARS-CoV-2

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

33852936

Citation

Posch, Wilfried, et al. "C5aR Inhibition of Nonimmune Cells Suppresses Inflammation and Maintains Epithelial Integrity in SARS-CoV-2-infected Primary Human Airway Epithelia." The Journal of Allergy and Clinical Immunology, vol. 147, no. 6, 2021, pp. 2083-2097.e6.
Posch W, Vosper J, Noureen A, et al. C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2-infected primary human airway epithelia. J Allergy Clin Immunol. 2021;147(6):2083-2097.e6.
Posch, W., Vosper, J., Noureen, A., Zaderer, V., Witting, C., Bertacchi, G., Gstir, R., Filipek, P. A., Bonn, G. K., Huber, L. A., Bellmann-Weiler, R., Lass-Flörl, C., & Wilflingseder, D. (2021). C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2-infected primary human airway epithelia. The Journal of Allergy and Clinical Immunology, 147(6), 2083-e6. https://doi.org/10.1016/j.jaci.2021.03.038
Posch W, et al. C5aR Inhibition of Nonimmune Cells Suppresses Inflammation and Maintains Epithelial Integrity in SARS-CoV-2-infected Primary Human Airway Epithelia. J Allergy Clin Immunol. 2021;147(6):2083-2097.e6. PubMed PMID: 33852936.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2-infected primary human airway epithelia. AU - Posch,Wilfried, AU - Vosper,Jonathan, AU - Noureen,Asma, AU - Zaderer,Viktoria, AU - Witting,Christina, AU - Bertacchi,Giulia, AU - Gstir,Ronald, AU - Filipek,Przemyslaw A, AU - Bonn,Günther K, AU - Huber,Lukas A, AU - Bellmann-Weiler,Rosa, AU - Lass-Flörl,Cornelia, AU - Wilflingseder,Doris, Y1 - 2021/04/20/ PY - 2020/11/11/received PY - 2021/03/25/revised PY - 2021/03/29/accepted PY - 2021/4/15/pubmed PY - 2021/6/16/medline PY - 2021/4/14/entrez KW - SARS-CoV-2 KW - anaphylatoxin receptors KW - complement KW - primary human airway epithelial cells SP - 2083 EP - 2097.e6 JF - The Journal of allergy and clinical immunology JO - J Allergy Clin Immunol VL - 147 IS - 6 N2 - 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/33852936/C5aR_inhibition_of_nonimmune_cells_suppresses_inflammation_and_maintains_epithelial_integrity_in_SARS_CoV_2_infected_primary_human_airway_epithelia_ DB - PRIME DP - Unbound Medicine ER -