Impact of SARS-CoV-2 on the barrier function of the airway epithelium

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Clinical trails revealed that glucocorticoids like dexamethasone reduce the mortality of severely diseased Covid-19 patients, presumably because of their immune modulatory effects. The airway epithelium forms the surface of the conductive airways, is a primary site of SARS-CoV-2 exposure and constitutes a barrier for viral invasion and dissemination into the organism. The ability of this barrier to prevent virus invasion depends on its cellular integrity and on tight junctions that seal the lateral intercellular space between adjacent epithelial cells in order to prevent leaking of solutes and water. Damage of tight junctions as a result of virus infection might play a key role in the breakdown of the epithelial barrier and promote severe lung damage.We demonstrated that glucocorticoids stabilize protein assembly and tightening of tight junctions by promoting incorporation of claudin 8. The latter function might contribute to the beneficial effect of glucocorticoids in Covid-19 treatment. Thus, the project has the following aims: i) to resolve the impact of SARS-CoV-2 on airway epithelial tight junctions, ii) to characterize the changes in epithelial transport and airway surface liquid homeostasis during SARS-CoV-2 infection and iii) to elucidate, whether glucocorticoids prevent SARS-CoV-2 induced tight junction damage.The investigations will be performed primarily in an in-vitro model of the airway epithelium that bases on human primary lung epithelial cells, which will be cultivated at an air-liquid interface. This model resembles the cellular composition as well as the functional properties of the airway epithelium and allows to study its functional and biophysical properties. The proposed studies on the impact of SARS-CoV-2 on tight junctions and epithelial transport properties will provide new insights into the mechanisms of SARS-CoV-2 induced lung damage and the mode of action of glucocorticoids.