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 Jun;147(6):2083-2097.e6. doi: 10.1016/j.jaci.2021.03.038. Epub 2021 Apr 20.


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.

Keywords: SARS-CoV-2; anaphylatoxin receptors; complement; primary human airway epithelial cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bronchi / immunology*
  • Bronchi / pathology
  • Bronchi / virology
  • COVID-19 / immunology*
  • COVID-19 / pathology
  • COVID-19 / virology
  • Cell Line
  • Complement Activation*
  • Complement C3 / immunology
  • Cytokines / immunology
  • Epithelial Cells / immunology*
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • Humans
  • Inflammation / immunology
  • Inflammation / pathology
  • Receptor, Anaphylatoxin C5a / immunology*
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / pathology
  • Respiratory Mucosa / virology
  • SARS-CoV-2 / immunology*


  • C3 protein, human
  • C5AR1 protein, human
  • Complement C3
  • Cytokines
  • Receptor, Anaphylatoxin C5a