SUMMARY Clinical sequelae of COVID-19 patients include not only acute respiratory distress syndrome (ARDS), but also often acute kidney injury and heart failure. These pathologies share endothelial activation as a common underlying early response to injury, and endothelial cells express high levels of angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV-2. Activated endothelium not only attracts and promotes leukocyte infiltration into tissues and contributes to the cytokine storm resulting in capillary leakage and edema, but is also prothrombotic. Together, these mechanisms result in tissue inflammation and ischemia, leading to organ failure. Our laboratory discovered that polymerase delta interacting protein 2 (Poldip2) is a novel and important regulator of inflammation, endothelial permeability and potentially coagulation in mice. Mice heterozygous for Poldip2 are largely protected from lipopolysaccharide (LPS)- or P. aeruginosa-induced ARDS. Here, we hypothesize that Poldip2 may be a novel target for treatment of SARS-CoV-2-infected individuals, as downregulation of Poldip2 not only reduces ARDS complications such as edema and the cytokine storm, but also potentially may inhibit thrombosis. To test this hypothesis, we propose to treat SARS-CoV-2-infected mice with an anti-cancer agent undergoing clinical trials that we have recently shown to reduce Poldip2 levels and restore endothelial barrier function. In the first Aim, we will use this agent to downregulate Poldip2 and test its ability to preserve endothelial barrier function and reduce inflammation in response to SARS-CoV-2 infection in mice. The second aim will focus on determining the effect of the anticancer agent and genetic ablation of Poldip2 on basal coagulation and that induced by SARS-CoV-2 infection. We anticipate that pharmacological downregulation of Poldip2 will represent a promising new treatment for COVID-19 patients that can be rapidly translated to the clinic.

NARRATIVE Endothelial activation causes inflammation and clotting, which are found in COVID-19 patients that develop acute respiratory distress syndrome (ARDS). In this project, we will test the ability of a new investigational cancer drug that targets a protein called polymerase delta interacting protein-2 (Poldip2) to control inflammation and reduce blood clotting in a mouse model of COVID-19 associated ARDS.