Pondering on Long Covid: Could Loss of ACE2 Receptors be Causative?

My hypothesis is that Long Covid is caused by shedding of ACE2 receptors leading to prolonged down regulation of ACE2, disturbances in the RAAS system, inflammation via RAAS inflammatory pathways, and increases in ROS (which triggers ME/CFS in some, but not all LC patients).

As a disclaimer, I’m a lawyer with no formal science background. I’m well aware of the impossible complexity of the immune system, cellular biology, metabolism, etc. and the unlikelihood of being right about much of anything regarding these topics. However, I’ve recently gone down a rabbit hole relating to Covid, shedding of ACE2 receptors, and the potential impact of the loss of ACE2 receptors. I’m having a hard time finding a reason the below hypotheses cannot be correct and am genuinely curious if there are obvious problems I’m overlooking. Put simply, don’t hesitate to tell me why none of this makes any sense if that’s the case

Below is a brief background on my post-viral illness history. I’ve included it because it has helped shaped my hypothesis.

I’ve had three post viral illness in my life. The first two (ages 18 and 37) followed respiratory infections and were similar to one another in terms of symptoms and duration. Both were slows climbs without relapses. I recovered from each at approximately 3 years. My blood pressure increased substantially and permanently after the first illness.

I caught COVID (confirmed) for the first time in late 2023. LC began a few weeks later with sudden shaking, nausea, pots, and neuro symptoms. My LC symptoms have a fair degree of overlap with the first two illness, but are quite different in several ways. I’ve recovered from LC to around 75% twice over 4 to 6 months. However, I’ve now had two LC relapses following mild respiratory infections (unknown whether covid). Each relapse re-initiated the entire set of LC symptoms and recovery timeline.

My symptoms in all of the above generally align with ME/CFS with one significant difference. I don’t experience PEM. For example, I have constant malaise and neurological issues, but I can lift weights without repercussions on a good day.

My ACE2 receptor hypothesis is largely based on this Johns Hopkins Cytokine Storm paper: https://doi.org/10.1073/pnas.2401968121

Essentially, the Johns Hopkins researchers looked at gene expression in those who suffered cytokine storms. The finding is that Covid induces shedding of ACE2 receptors. The resulting disturbance to the RAAS system then causes the RAAS system to send inflammatory signals, which cause widespread inflammation and modulate the immune system in ways that may be harmful. Those signals ultimately result in mitochondrial damages, unchecked ROS, and oxidative stress.

The above lead me ponder whether: (1) the same loss of ACE2 receptors and disturbance to the RAAS system might be responsible for LC symptoms; (2) whether the same might explain why Covid triggers ME/CFS.

I first looked to see how long it might take down regulated ACE2 receptors to upregulate after COVID. It seems we don’t know much l aside from the fact that ADAM17 cleaves ACE2 receptors as part the immune response to COVID. I did however, find this paper: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252799 as well as others that provide evidence of long term down regulation of ACE2 following Covid infection. One paper found elevated level of ACE2 precursors 8 months post-infection suggesting down regulated ACE2 receptors 8 months post-infection.

Next, I looked at where ACE2 is highly expressed in tissue. Interestingly, ACE2 is expressed in the hypothalamus as well as parts of the brainstem that control various autonomic functions.

Finally, I looked at what is probably true regarding LC. We know that: (1) LC behaves differently than other viruses and entry via ACE2 is not common amongst other coronaviruses; (2) LC is good at triggering ME/CFS and POTS; (3) Anecdotally, LC induced POTS is more likely to resolve than POTS caused by most other mechanism; (4) Anecdotally, it appears that many LC recoveries occur, if at all, between 18 months to 3 years; and (5) there are extensive reports of LC relapse following subsequent infection; (6) existing drugs do not seem to treat LC.

Synthesizing the above, could it all come down to the sustained loss of ACE2 receptors? Loss of ACE2 seems like a good candidate to explain transient POTS. Likewise, the duration of ACE2 down regulation seems as if it could potentially align with the duration of LC. Loss of ACE2 receptors in the brain and brainstem seem to align well with the odd neurological and autonomic symptoms that are common in LC. Relapse caused by reinfection would likely result in further cleavage of ACE2, which would explain relapse after re-infection. A deregulated RAAS system (due to ongoing ACE2 down regulation) might cause ongoing inflammation and immune disturbances similar to, but at a lower level, than what has been observed in cytokine storms. Finally, there are no existing drugs with good evidence of upregulating ACE2 in tissue.

Finally, I think there is a potential ME/CFS tie in. If we assume that a sustained innate immune response, or perhaps just sustained high oxidative stress, is the universal trigger for ME/CFS, then the Hopkins paper provides some interesting possibilities. First, assuming I’ve understood the paper correctly, the pathways affected by RAAS signaling begin to converge many of the same pathways implicated in Davis’/Phair’s Itaconate Shunt Hypthesis as well as the WASF3 finding as it related to PEM. The Johns Hopkins paper also discusses Covid induced damage to the lymphatic system, which inhibits adaptive immunity. Presumably, this inhibition results in a poor adaptive immune response and a sustained innate immune response. So, we have increased ROS via RAAS pathways and a sustained innate immune response via an inhibited adaptive immune response.

Many thanks in advance to all who read or comment.

 

Some interesting thoughts @Stuart79 but in my view you cannot do immunology by stringing together these high-level concepts like inflammation or innate immunity. You can string any words together you like one way or another. Real immunology depends on identifying which specific pathway is behaving differently in each situation.

So the biggest problem here for your theory is that in LC and ME/CFS there is no inflammation. That is a fact. We have good enough enough methods to look and there is no inflammation findable. Some of the mediators that are involved in inflammation might be acting alone in ME/CFS to produce symptoms without any inflammation but as soon as you try to explain things in terms of inflammation you have made the theory too vague to be testable.

I would also question what is meant by oxidative stress. This was a popular concept in the 1980s, linked to 'free radicals' later named 'reactive oxygen species'. It was thought in those days that they were important inflammatory mediators but it never really added up and by the 2000 I think most people realised that redox interactions are involved in lysosomal function, and also in eicosanoid pathways, but are not in themselves inflammatory mediators. There are still a few people going on about oxidative stress in review articles but old ideas take a long time to fade away in medicine.

The overarching problem we have now is that the literature is flooded with half-baked review articles from second-rate scientists wanting to make a noise and often harking back to old ideas. People have lost touch with the direct experimental evidence base that drove immunology in its infancy in the 1970s.

Damage to the lymphatic system would have no effect on adaptive immunity in general - at least not without some gross signs of lymphoedema, which are not present in LC. You cannot separate adaptive and innate immune responses any more than you can separate the function of frying pans and stoves. All this yin and yang talk about cytokine balance and arms of the immune system is empty mantra I am afraid. Understanding diseases requires a knowledge of specific pathway alterations and nothing else.

 

Thank you, @Jonathan Edwards. I always enjoy reading your posts and greatly appreciate your feedback. As a lay person, it’s very interesting, and super helpful, to see how an expert in the field thinks through these things.

Perhaps the narrower question I should have asked is this: Do we have any reason to believe, or disbelieve, that the loss of ACE2 receptors could cause long covid symptoms?

From what I gather, we know that: (1) Covid enters VIA ACE2 resulting in shedding of receptors; (2) Ang1 is elevated for many months after Covid implying ongoing ACE2 problems; and (3) the only other viruses known to enter via ACE2 are SARS, MERS, and one particular coronavirus (common cold) strain that is purportedly mild.

I think the essence of what I’m getting at is we have three virus’s that enter via ACE2 and often result in post viral syndromes. We also have reason to suspect sustained downregulation of ACE2 following Covid infection. So, would it not make sense to look into whether the loss of ACE2 receptors is the problem before looking at things like viral persistence, T-cell abnormalities, etc. that may or may not have any relevance at all?

 

`I don't know about ACE receptors specifically but my understanding is that most cell surface receptors are recycled or resynthesises very quickly - over minutes, hours or at most days. If there is a longer receptor deficit then it ought to be due to some other signal such as a cytokine or hormone suppressing receptor replacement. The question then is why we would attribute symptoms to that receptor deficit rather than maybe a range of other changes induced by the hormone. And what was controlling the hormone?