Figure 4.

Schematic diagram of downstream effects of epithelial damage in COVID-19. COVID-19 infection occurs when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to surface receptor angiotensin-converting enzyme 2 (ACE2) on pulmonary epithelial cells, stimulating the release of PAMPs, DAMPs and cytokines/chemokines into the cellular microenvironment and causing the recruitment and activation of innate immune cells followed by adaptive immune cells to the site of damage. In most circumstances, the immune response is capable of resolving infection and restoring tissue homeostasis. However, this process can become dysregulated, resulting in a hyper inflammatory response termed a ‘cytokine storm’, which can cause further damage to the pulmonary epithelium in a positive feedback loop. Damaged epithelial cells stimulate the release of more pro-inflammatory chemokines/cytokines and DAMPs, exacerbating epithelial cell damage and death. Cytokine storm syndrome is considered to be one of the major causes of acute respiratory distress syndrome (ARDS), endothelial dysfunction, sepsis and multiple-organ dysfunction in humans, causing a rapid decline in lung function and ultimately death. Created using Biorender.com.