C5aR inhibition of non-immune 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

Background Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe SARS-CoV-2 infections and is associated with enhanced pathogenicity and mortality. Objective Complement hyper activation promotes lung injury and was observed in patients suffering from MERS-CoV, SARS-CoV-1 and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells upon exposure to SARS-CoV-2 in terms of complement C3-mediated effects. Methods For this, we used highly differentiated primary human 3D tissue models infected with SARS-CoV-2 patient isolates. Upon 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 TEER 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 3D cultures secreted significantly higher levels of C3a and the pro-inflammatory cytokines IL-6, MCP-1, IL-1α and RANTES. Conclusion Crucially, we illustrate here for the first time, that targeting the anaphylotoxin receptors C3aR and C5aR in non-immune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19.