SARS-CoV-2-induced endothelial cell dysfunction: mechanisms and therapeutic approaches

Since the beginning of vaccine development, spreading of Severe Acute Respiratory Syndrome Virus type 2 (SARS-CoV-2) variants, characterized by multiple mutations in their Spike glycoproteins, have risen concern over vaccine efficacy; thus, calling for the urgent need of alternative therapeutic approaches. Beside vaccine, only few effective small-molecules directly targeting SARS-CoV-2 have been identified. The search of new therapeutic targets and potential treatment for COVID-19 is extremely important in order to realize a prompt approach to inhibit SARS-CoV-2 entry and COVID-19-related diseases. The commonly reported symptoms of SARS-CoV-2 infection (COVID-19) include cough, fever and shortness of breath, even if extra-pulmonary signs may also be present. When COVID-19 progresses from mild to severe disease, patients may develop an acute respiratory distress syndrome (ARDS), which reflects dramatic microvascular endothelial cell (mEC) dysfunction involving changes in vascular permeability, inflammation, activation of procoagulant pathways and disruption of alveolar-capillary barrier. The most common observed comorbidities in COVID-19 patients are represented by systemic hypertension, diabetes and obesity, in which endothelial dysfunction play a key role.

Recently, we demonstrated that SARS-CoV-2 gains access into primary human lung mECs (HL-mECs) lacking Angiotensin-converting enzyme 2 (ACE2) expression through a conserved Arg-Gly-Asp (RGD) motif. The latter is the smallest sequence necessary to proteins to bind integrins. Integrins represent a gateway of entry for many viruses. Recently, we highlighted the αvβ3 integrin as the main molecule responsible for SARS-CoV-2 infection of HL-mECs via a clathrin-dependent endocytosis. Following its entry, SARS-CoV-2 remodels cell phenotype and promotes angiogenesis in the absence of productive viral replication. Interestingly, the inhibition of Spike/αvβ3 interaction was sufficient to counteract the SARS-CoV-2-sustained EC dysfunction. It is worth to note that, the anti-Spike antibodies evoked by vaccination were neither able to impair Spike/integrin interaction nor to prevent SARS-CoV-2 entry into HL-mECs.

The primary purpose of this project is to clarify the mechanisms involved in EC dysfunction during COVID-19 by combining different expertise. We will identify, by drug-repurposing, the treatment to disrupt virus-host interaction, to ameliorate the follow-up of COVID-19 patients, and to decrease morbidity, mortality and also public costs. Moreover, this project will increase the understanding of endothelial dysfunction assessment tools allowing a prompt transition from bench-to-bedside.