ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients, 2024, Song et al.

ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients
Yufeng Song; Regan Myers; Frances Mehl; Lila Murphy; Bailey Brooks; Jeffrey M. Wilson; Alexandra Kadl; Judith Woodfolk; Steven L. Zeichner

Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for the SARS-CoV-2 spike protein receptor-binding domain (RBD) is angiotensin-converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have a negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity—ACE2-like abzymes. To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn 2+ for activity.

However, we found that the plasma from some patients studied could specifically cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium EDTA anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn 2+ was added or the plasma was diluted to decrease EDTA concentration. After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis.

IMPORTANCE
We provide what we believe to be the first description of angiotensin converting enzyme 2 (ACE2)-like enzymatic activity associated with immunoglobulin in COVID-19 patients. COVID-19 includes many puzzling clinical features that have unclear pathogenesis, including a hyperinflammatory state, abnormalities of the clotting cascade, and blood pressure instability. We hypothesized that some patients with COVID-19 patients may produce antibodies against SARS-CoV-2 with enzymatic activity, or abzymes, that target important proteolytic regulatory cascades. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds ACE2 on the surface of the future host cell. This means that the RBD has a negative molecular image of ACE2. We hypothesized that some antibodies produced against the RBD would have, in turn, a negative molecular image of the RBD sufficiently similar to ACE2 to have ACE2-like catalytic activity. In other words, some anti-RBD antibodies would be ACE2-like abzymes. Abzymes elicited by SARS-CoV-2 infection have the potential to affect host physiology.

Link | PDF (mBio) [Open Access]

 

I have problems trying to understand the meaning of this study and haven't read much of it yet but I have some immediate questions:

If you know you're looking for ACE-2 antibodies how hard would it be to find them or asses their functionality in different patient groups?

Wouldn't they show up in the REAP analysis Iwasaki did or is this whole abzyme + Zn 2+ process completely different?

Seems like a decent enough study to me, or at least there is a control group and the authors admit possible alternative explanations and many different short-comings in the limitations sections including

and

Whilst ACE-2 might be somewhat SARS-COV-2 specific I wonder whether one might just see something similar for the appropriate target for a different viral infection (the authors state "Some other viruses also have evolved to use enzymes located on the target host cell surface as their receptors, so it is conceivable that those other viral infections may also elicit clinically problematic anti-viral antibodies.")? Most importantly one would probably have to know whether these abzymes can persist after the acute infection and if they are tied to symptomology.

Is this similar to what @Jonathan Edwards proposed here or is this whole abzyme talk some statistically driven immunobabble without a connection to reality that is entirely different?

Other than that I know of two groups who are using mouse models where IgG of different patient groups is transferred to mice, the model by den Dunnen and Iwasaki recently presented first results of her own mouse model (https://www.harveysociety.org/videos/video.php?series=117&lecture=4) which also includes a group similar to the one here, i.e. an acute Covid patient group.

 

I think again that this is trying to be too clever and is unlikely ever to pan out to an established effect. They do not report purifying an Ig fraction that actually has the activity proposed - which would be the acid test. That last step is always the most difficult but if you don't do it the study always remains inconclusive.

If there were antibodies with ACE2 activity (in effect the opposite of antibodies to ACE2) then I would expect something like severe hypertensive crisis, which as fa as I know is not a feature of Covid infection.

It may be salutary to remember that playing around in immunology labs may well have been the reason for the pandemic in the first place. And the pandemic was shown to be entirely controllable in May 2020. But nobody wanted to know...