Coronavirus disease-2019 (COVID-19) is a global pandemic caused by infection with severe acute respiratory syndrome virus-2 (SARS-CoV-2). As of February 2022, COVID-19 has affected over 420 million people and nearly 6 million have died. Acute respiratory distress syndrome (ARDS), characterized by pulmonary microvascular thrombosis and capillary leak, infiltration of immune cells into the lungs, and inflammatory cytokine release, is an all-too-common outcome of SARS-CoV-2 infection, particularly early in the pandemic before vaccines were widely available. While subsequent waves caused by viral mutants have had, varied severity, spread, and symptomology, cardiopulmonary complications remain a hallmark of severe acute COVID-19 and are prevalent in those with post-acute sequelae of COVID-19 (PASC, or long COVID). How SARS-CoV-2 drives these outcomes remain elusive, and is a topic of considerable research.
To infect the host, SARS-CoV-2 uses its spike protein to bind angiotensin converting enzyme 2 (ACE2) on target cells. This interaction results in the down-regulation of ACE2 surface expression and impairs ACE2 function. ACE2 cleaves angiotensin (AT)-1 and AT-2, and physiologically functions as a homeostatic regulator of blood pressure (Lu et al., J Biol Chem 2020). ACE2 is also one of the inactivating proteases responsible for neutralizing about 80–90% of the circulating bradykinin (BK) in the pulmonary vascular bed (Dragovic et al., Am Rev Resp Dis, 1993). Excess BK potentially facilitates capillary dilation, leaking of protein rich exudates and organ failure (Gonzales et al., Austin J Vasc Med. 2015). In inflammatory settings, BK engages its dedicated receptors, disrupting the capillary endothelial barrier function and facilitating the entry of immune cells into pulmonary interstitial tissue space (Kenne et al., FASEB, 2019, Finsterbusch et al., J Exp Med, 2014). Thus, a reduction in ACE2 potentially dysregulate both AT-2 and BK homeostasis contributing to pathological changes in the respiratory tract (Samavati et al., Front Cell Infect Microbiol, 2020).
Two studies presented at the 2022 Conference on Retroviruses and Opportunistic Infections (CROI) investigated the mechanisms of how SARS-CoV-2 spike protein contributes to thrombosis. First, Dr. Mauricio Montano gave an oral presentation describing direct binding of spike protein to plasma fibrinogen conferring structural modifications of fibrin polymers with increased thrombogenic potentials. In a second study from our own group, we found that the ACE2 was significantly reduced in the alveolar lining of SARS-CoV-2 infected lungs and when human pulmonary alveolar epithelial cells and aortic endothelial cells were exposed to spike protein ex vivo. In addition, we showed that BK and spike protein trigger the release of IL-6 and longer exposure induced pan-caspase activation, PARP-1 cleavage, and apoptosis of human aortic endothelial cells. On the other hand, BK alone caused calcium relocation and endothelial dysfunction as characterized by increased of von Willibrand Factor (vWF) and decreased of Krüppel-like Factor 2 (KLF2) levels in endothelial cells but did not adversely affect their viability (Panigrahi et al., CROI 2022; Abstract 193). These studies provide evidence that spike protein alone can mediate adverse effects on vascular cells and coagulation elements. Taken together, these studies show that SARS-CoV-2 causes complex detrimental effects on microvascular homeostasis that contribute to microvascular thrombosis and organ dysfunction. Interference with interactions of spike protein or BK with endothelial cells may serve as an important strategy to stabilize microvascular homeostasis in COVID-19 disease. A version of our study with more details was recently published in Microbiology Spectrum (Panigrahi et al., 2021). In the future, investigating these mechanisms of pathogenesis may provide rationale for novel intervention strategies, which could limit microvascular events associated with SARS-CoV-2 infection and long COVID.
Soumya Panigrahi, Michael L. Freeman, and Scott F. Sieg
Department of Infectious Diseases
Case Western Reserve University