Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences

Abstract

COVID-19 causes persistent endothelial inflammation, lung and cardiovascular complications. SARS-CoV-2 utilises the catalytic site of full-length membrane-bound angiotensin converting enzyme 2 (ACE2) for cell entry causing downregulation of tissue ACE2. We reported downregulation of cardiac ACE2 is associated with increased plasma ACE2 activity. In this prospective observational study in recovered COVID-19 patients, we hypothesised that SARS-CoV-2 infection would be associated with shedding of ACE2 from cell membranes and increased plasma ACE2 activity. Methods We measured plasma ACE2 catalytic activity using a validated, sensitive quenched fluorescent substrate-based assay in a cohort of Australians aged 18 years and over who had recovered from mild, moderate or severe SARS-CoV-2 infection (positive result by PCR testing) (n=66) and age and gender matched uninfected controls (n=70). Serial samples were available in 23 recovered SARS-CoV-2 patients. Results Plasma ACE2 activity at a median of 35 days post-infection [interquartile range 30-38 days] was 97-fold higher in recovered SARS-CoV-2 patients compared to controls (5.8 [2-11.3] vs. 0.06 [0.02-2.2] pmol/min/ml, p<0.0001). There was a significant difference in plasma ACE2 activity according to disease severity (p=0.033), with severe COVID-19 associated with higher ACE2 activity compared to mild disease (p=0.027). Men (n=39) who were SARS-CoV-2 positive had higher median plasma ACE2 levels compared to women (n=27) (p<0.0001). We next analysed whether an elevated plasma ACE2 activity level persisted following SARS-CoV-2 infection in subjects with blood samples at 63 [56-65] and 114 [111-125] days post infection. Plasma ACE2 activity remained persistently elevated in almost all subjects, with no significant differences between timepoints in post-hoc comparisons (p>0.05). Discussion This is the first description that plasma ACE2 activity is elevated after COVID-19 infection, and the first with longitudinal data indicating plasma ACE2 activity remains elevated out to a median of 114 days post- infection. Larger studies are now needed to determine if persistent elevated plasma ACE2 activity identifies people at risk of prolonged illness following COVID-19.

Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

“…Shedding was the proposed mechanism behind high plasma ACE2 activity after COVID-19 (34), and virus-induced shedding of ACE2 has previously been demonstrated in several studies of SARS-CoV (14-16, 39). Shedding of ACE2 in airway epithelial cells occurs constitutively but is also inducible (6, 14, 16, 40).…”

“…Male sex deviated from this pattern, with clearly higher sACE2 levels in men than in women. The study by Patel et al and two studies of heart failure also found higher circulating sACE2 antigen/activity in men as compared to in women (34, 46, 47) suggesting that ACE2 shedding may be higher in men under pathological conditions. It warrants further investigation if increased shedding or high sACE2 levels contribute to more severe disease in men.…”

“…To our knowledge, sACE2 antigen has not been previously measured in the acute phase of COVID-19. A recent study showed plasma ACE2 activity to be strongly elevated one month after COVID-19 compared with controls (34). In contrast with our results, levels were maintained for several months in patients who were followed up repeatedly.…”

Increased angiotensin-converting enzyme 2, sRAGE and immune activation, but lowered calcium and magnesium in COVID-19: association with chest CT abnormalities and lowered peripheral oxygen saturation

“…Recent studies showed increased levels of angiotensin-converting enzyme 2 (ACE2) following SARS-CoV-2 infection (Patel et al ., 2021), and a case report showed very high ACE2 levels in a critically ill COVID-19 patient (Nagy et al ., 2021). ACE2 is a common binding site for both SARS-CoV and SARS-CoV-2 (Zhu et al ., 2018, Hoffmann et al ., 2020).…”

Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients

“…Plasma ACE2 activity is elevated in patients after COVID-19 infection compared to healthy controls. 14 Further, ACE2 plasma concentrations have been measured in patients with risk factors for severe COVID-19 disease. In patients with heart failure, plasma levels of ACE2 were higher in men than in women which could explain the higher incidence and fatality rate of COVID-19 in men.…”