SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction

Abstract

Infections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses.To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells.Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear.In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.

A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics

“…Our first results with drugs in Airway Chips were obtained three weeks later, and we published a preprint describing our findings on April 13, 2020 47 . Subsequent preprints and publications from other laboratories also have described the utility of using Organ Chips to study infection and inflammation responses caused by SARS-CoV-2 infection 48 – 50 . However, all of these reports have used chips lined with human primary alveolar epithelial cells or cell lines rather than airway epithelium that are the primary target of initial infection in vivo , and none explored drug repurposing.…”

Human lung-on-chips: Advanced systems for respiratory virus models and assessment of immune response

“…Notably, their findings verified the pulmonary surfactant secretion from the alveolus chip, which is crucial for the integrity of the epithelial barrier along with the host defense. In another study conducted by Deinhardt-Emmer et al, 88 an in vitro human-specific alveolus-on-a-chip model was utilized to recapitulate alveolar architecture and function along with SARS-CoV-2 alveolar infection. To investigate the interaction between endothelial and epithelial cells along with the viral effects on alveolar barrier integrity and inflammatory responses, Calu-3 epithelial and human umbilical vascular endothelial cells with cocultured mononuclear cells (macrophages isolated PBMCs) were used.…”

Prognostic value of von Willebrand factor and ADAMTS13 in patients with COVID-19: A systematic review and meta-analysis

“…A prevalent view holds that SARS-CoV-2 enters ECs directly by binding to the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor [89,95,96]. But more recent studies have disputed the expression of ACE2 on ECs in postmortem COVID-19 tissues and in cultured ECs, and they suggest that the endotheliopathy is induced by pro-inflammatory cytokine milieu, complement activation, or tissue hypoxia [90,[97][98][99]. Ma et al [100] recently reviewed and summarized that ROS, VEGFA/VEGFR2, and HMGB1/RAGE/TLR4 are potential J o u r n a l P r e -p r o o f Journal Pre-proof signaling pathways that involved in the COVID-19-associated endotheliopathy.…”