COVID-19 is a viral respiratory tract infection caused by SARS-CoV-2. Initial infection with the first wave strain and subsequent variants, up to and including the Delta variant were associated with considerable acute lung injury (ALI) and fibrotic sequelae. However, the Omicron variant has been associated with less ALI, although whether this is due to immunity or intrinsic differences in the biology of the virus is not known. It is important to understand the mechanisms of alveolar damage during the SARS-CoV-2 infection to prevent the development of ALI and any subsequent complications. The parent SARS-CoV-2 spike protein contains a cryptic RGD motif that is exposed upon binding to the ACE2 receptor, which is lost in Omicron/BA.2 and subsequent variants. We therefore wanted to understand the role of the RGD motif in viral cell entry and cellular pathology. Using a solid phase binding assay we show that the parent SARS-CoV-2 spike protein can bind the αvβ6 integrin in a concentration and EDTA dependent manner (Calver J, et al. Thorax 2021; 76:A22-A23). Using a pseudoviral assay we demonstrate that expression of the αvβ6 integrin can augment ACE2 mediated viral cell entry and using immunocytochemistry we demonstrate co-localisation of the spike protein, ACE2 and αvβ6. BA.2 Omicron spike protein doesn't contain the RGD motif and we are studying whether this mutation has an effect on the cell internalisation. Our prior data have suggested people with conditions associated with high levels of the αvβ6 integrin were more likely to develop severe complications of COVID-19 supporting a role for RGD binding in the pathogenesis of COVID-19 ALI. These data might indicate that the reduction in ALI following the omicron variant is due in part to reduced ability to engage alveolar integrins.