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 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.
['Posch|Wilfried|W|', 'Vosper|Jonathan|J|', 'Noureen|Asma|A|', 'Zaderer|Viktoria|V|', 'Witting|Christina|C|', 'Bertacchi|Giulia|G|', 'Gstir|Ronald|R|', 'Filipek|Przemyslaw A|PA|', 'Bonn|Günther K|GK|', 'Huber|Lukas A|LA|', 'Bellmann-Weiler|Rosa|R|', 'Lass-Flörl|Cornelia|C|', 'Wilflingseder|Doris|D|']
D001980:Bronchi D000086382:COVID-19 D002460:Cell Line D003167:Complement Activation D003176:Complement C3 D016207:Cytokines D004847:Epithelial Cells D006801:Humans D007249:Inflammation D044087:Receptor, Anaphylatoxin C5a D020545:Respiratory Mucosa D000086402:SARS-CoV-2
SARS-CoV-2 complement primary human airway epithelial cells anaphylatoxin receptors