Integrated renin angiotensin system dysregulation and immune profiles predict COVID-19 disease severity in a South African cohort

Renin-angiotensin system (RAS) dysregulation is an important component of the complex pathophysiology of SARS-CoV-2 and other coronavirus infections. Thus, angiotensin-converting enzyme 2 (ACE2), the entry receptor and key to the alternative RAS, was proposed as a severity/prognostic biomarker for risk-stratification. However, experimental RAS data from diverse cohorts are limited, particularly analyses integrating RAS with immune biomarkers. Participants (n = 172) in Cape Town were sampled longitudinally (including a recovery timepoint [> 3-month]), across WHO asymptomatic to critical severity. Using fluorometric assays and LC-MS/MS RAS Fingerprinting^®, results show serum ACE1 activity significantly decreases with increasing COVID-19 severity (P < 0.01) and mortality (P < 0.05), while increased ACE2 activity is associated with worse severity (P < 0.01). Neither enzyme activity correlates with viral load proxy or nasal ACE mRNA levels. ACE1 and ACE2 activities were the most effective severity biomarkers compared to 96 established immune markers obtained via proximity extension assay, as demonstrated by principal component analysis. A multivariate variable selection model using random forest classification identified biomarkers discriminating COVID-19 severity (AUC = 0.82), the strongest being HGF, EN-RAGE, cathepsin L. Adding ACE1 activity and anti-SARS-CoV-2 antibody titres improved differentiation between ambulatory and hospitalised participants. Notably, RAS dysregulation has unique severity associations in coronavirus infections with implications for treatment and pathophysiological mechanisms.