Krishna Sriram (UC San Diego)| Paul Insel (UC San Diego)
The COVID-19 pandemic has created an urgent need for therapeutics based on the pathobiology of SARS-CoV-2 infection, which primarily produces pulmonary disease: injury to distal airways and alveoli via binding of the virus to ACE2 (angiotensin converting enzyme-2) expressed on airway epithelia and type-2 pneumocytes. In severe cases, alveolar injury is accompanied by increasing inflammation and coagulopathy, further enhancing tissue injury. This 'thromboinflammation' contributes to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in severe COVID-19 cases and is associated with secondary infection and cytokine storm, which can lead to multiple organ failure, morbidity and mortality. We present an analysis of pathways that drive COVID-19 pathobiology, in particular key pathways that link alveolar pathology with subsequent thromboinflammation and that together, drive disease progression towards ALI , ARDS, increased morbidity and death.
The binding of SARS-CoV-2 to ACE2 in alveoli leads to internalization of the virus-protein complex and inhibition of ACE2 activity. ACE2, a critical regulator of angiotensin signaling, reduces ANGII (angiotensin 2)-mediated effects and increases signaling by MAS1 receptors. ANGII (via its receptors, in particular AGTR1) drives an inflammatory, apoptotic and pro-fibrotic phenotype in the lung; MAS1 counters these effects. ACE2 is thus a key regulator of pulmonary inflammation/injury: dysregulation of ACE2 produces pulmonary pathology that involves interplay of multiple cell types, including pneumocytes, endothelial cells, fibroblasts and inflammatory cells. The resulting inflammation initiates the coagulation cascade, especially by release of tissue factor, which leads to thrombin formation and platelet activation. Thrombin also exerts pathological effects on other cell types in the lungs (e.g., pneumocytes and fibroblasts) via proteinase-activated receptors (PARs), further underscoring the interaction between coagulation and alveolar injury. Alveolar inflammation also leads to release of ADP (adenosine diphosphate) and platelet activation by purinergic (P2Y) receptors. In turn, platelet activation leads to further inflammation, creating a thrombinflammatory positive feedback loop. In addition, complement signaling is engaged: proteases in the coagulation cascade cleave C3 and C5 to C3a and C5a, respectively, further contributing to platelet and inflammatory cell activation. Crosstalk between these three sets of pathways thus drives pathological feedback loops.
These mechanisms of COVID-19 pathobiology suggest therapeutic approaches. Such approaches include inhibitors of ANGII signaling (e.g., ACE1 inhibitors or angiotensin receptor blockers), MAS1 agonists, and agents that blunt platelet activation, such as inhibitors of thrombin and/or PAR receptors and antiplatelet agents such as P2Y12 inhibitors. PAR (and, to a more limited degree, P2Y12) inhibitors have the potential to blunt multiple aspects of COVID-19 host pathobiology through effects on numerous cell types. We propose that such approaches may improve the course of COVID-19 patients and merit pre-clinical studies and clinical trials, including with approved drugs that might be repurposed.