European Respiratory Journal
Mirjam Kiener, Lea De Maddalena, Nuria Roldan, George N. Thalmann, Thomas Geiser, Nina Hobi, Marianna Kruithof-De Julio
Abstract
COVID-19 is an infectious disease caused by the newly discovered coronavirus named SARS-CoV-2. The virus enters the body through the airways by exploiting the angiotensin-converting enzyme 2 (ACE2) and serine proteinase TMPRSS2. Thus, especially lung epithelial cells are attacked by the virus. In the distal lung, the virus infection leads to life-threatening alveolar damage and cytokine storm. Many excellent clinical studies described the pathology of COVID-19 progression in patients. However, impactful in vitro studies are still missing due to the exceptional difficulty to model the alveolar setting in vitro. Here, we introduce two advanced models based on organoids and lung-on-chip (LOC) technology. The models derived from primary alveolar epithelial cells were characterized by fluorescence imaging and gene expression. Barrier function and cell polarity were assessed by confocal microscopy of tight junction and transporter proteins. We showed that the LOC model and the newly developed organoids preserve alveolar type II specific markers (SP-C and HTII-280). In both models we could detect relevant amounts of ACE2 and TMPRSS2 mRNA as compared to whole lung extracts.
As a next step we will optimize the infection titer for both systems to further analyze transcriptomic changes upon SARS-CoV-2 infection. The here presented advanced in vitro models, recapitulating the distal lung, serve as complementary SARS-CoV-2 lung infection models. The LOC model will allow to simulate alveolar breakdown and cytokine storm whereas the organoid models will facilitate high-content drug screening.
