ACE2 expression in PBMC and plasma markers of vasculopathy and fibrosis during early COVID – implications for post-COVID conditions

Background: Severe COVID is uncommon, restricted to 19% of the population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether variable expression of angiotensin converting enzyme 2 (ACE2) in blood might identify this difference in risk. Methods: The study was IRB-approved, comparing patients hospitalized with severe COVID to healthy controls. A single blood sample was obtained within a day of admission. ACE2 RNA expression in blood cells was measured by RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-2 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10. Results: 48 subjects and 72 controls were recruited. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID but common in healthy controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculitis (MMP-9) were also elevated. ACE2 RNA expression during severe COVID often responded within hours to convalescent plasma. By analogy to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID (the renin-angiotensin system (RAS), inflammation, fibrosis and vasculopathy) initiate or promote post-COVID conditions (PCC) in susceptible individuals. These may respond to convalescent plasma or its derivatives, fresh-frozen plasma or IVIG. Conclusions: This work is hypothesis-generating, elucidating biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.