Steroid hormone receptors and regulation of ACE2 and COVID-19 disease outcomes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a worldwide pandemic and social and economic upheaval. To date, SARS-CoV-2 has infected more than 620 million people worldwide, and more than 6.5 million deaths have been reported. Angiotensin-converting enzyme type 2 (ACE2) was identified as the receptor for SARS-CoV-2 and the mechanism whereby SARS-CoV-2 enter the cell. We now have a much clearer understanding of the mechanisms controlling the cleavage of SARS-CoV-2 spike proteins, binding of the virus to ACE2, and the impact of SARS-CoV-2 on infected cells. ACE2 is a key component of the physiological renin-angiotensin-aldosterone system (RAAS) where it opposes the action of angiotensin-converting enzyme type 1 (ACE1) and the pressor arm of the RAAS. Inhibitors of the RAAS are common therapies for hypertension and cardiovascular disease and upregulation of ACE2 is an important part of their therapeutic action, opposing the pressor actions of ACE1. Given the high mortality from SARS-CoV-2 in older people and those with cardiovascular disease, concerns were raised that ACE1 inhibitors could increase susceptibility to SARS-CoV-2 infection. However, multiple clinical and mechanistic studies have now negated this concern. Importantly, sexual dimorphism in response to SARS-CoV-2 infection is apparent, with men suffering greater morbidity and mortality, raising the question of the role that sex steroids and their receptors may play in determining the risk of serious COVID-19 disease. The synthetic glucocorticoid dexamethasone was one of the first and most effective therapies identified to significantly reduce death and time to recovery in severe COVID-19 disease, reflecting the critical role of corticosteroids in response to critical illness. This chapter reviews the role of corticosteroids, their receptors, and other members of the steroid hormone receptor family in the regulation of ACE2, SARS-CoV-2 infection, and COVID-19 disease.