Neutrophilic inflammation promotes SARS-CoV-2 infectivity and augments the inflammatory responses in airway epithelial cells

Abstract

IntroductionIn response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre- existing co-morbidities correlating to incidence to severe COVID-19 are associated with chronic airway neutrophilia. Furthermore, examination of COVID-19 explanted lung tissue revealed a series of epithelial pathologies associated with the infiltration and activation of neutrophils, indicating neutrophil activity in response to SARS-CoV-2 infection.MethodsTo determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory responses to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. This model was infected with live SARS-CoV-2 virus the epithelial response to infection was evaluated.ResultsSARS-CoV-2 infection of airway epithelium alone does not result in a notable pro-inflammatory response from the epithelium. The addition of neutrophils induces the release of proinflammatory cytokines and stimulates a significantly augmented proinflammatory response subsequent SARS-CoV-2 infection. The resulting inflammatory responses are polarized with differential release from the apical and basolateral side of the epithelium. Additionally, the integrity of the \epithelial barrier is impaired with notable epithelial damage and infection of basal stem cells.ConclusionsThis study reveals a key role for neutrophil-epithelial interactions in determining inflammation and infectivity.

SARS-CoV-2 Spike Proteins and Cell–Cell Communication Induce P-Selectin and Markers of Endothelial Injury, NETosis, and Inflammation in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for the Pathogenesis of COVID-19 Coagulopathy

“…Coronaviruses enter and infect target cells by binding their S-protein to cellular angiotensin-converting enzyme-2 (ACE2) [ 10 , 11 ], and human neutrophils [ 12 , 13 ] and endothelial cells [ 14 , 15 , 16 ] express ACE2. Because SARS-CoV-2 and its S-proteins are present in tissues and bodily fluids of infected patients and COVID-19 pathology includes endotheliopathy and leukocyte infiltration into the lungs [ 7 , 17 , 18 ], it is important to determine whether viral S-proteins directly contribute to these lung pathologies and whether leukocyte interactions with the vascular endothelium influence SARS-CoV-2-induced pathologies.…”