Review Inflammation-, immunothrombosis,- & autoimmune-feedback loops may lead to persistent neutrophil self-stimulation in long COVID, 2024, Thierry & Salmon

[SNT Gatchaman]

Inflammation-, immunothrombosis,- and autoimmune-feedback loops may lead to persistent neutrophil self-stimulation in long COVID
Alain R. Thierry; Dominique Salmon

Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post‐acute sequelae of COVID‐19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection.

This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS‐CoV‐2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS‐CoV‐2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection.

This continuous self‐stimulation of neutrophils leads, in turn, to systemic inflammation, micro‐thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications.

Link | PDF (Journal of Medical Virology) [Open Access]

 

[Murph]

NEGATIVE TAKE

This is a hypothesis paper. I made a comment in another thread recently about how easy it is to make up credible theories of mecfs. They're easy to generate. Useful, but cheap to make. What we really need is to match the rate of hypothesis generation with high-speed falsification: data. We need more constraints on hypotheses, more hurdles to clear and more hoops they need to jump through.

POSITIVE TAKE

When I look at a theory like this, I think about Trikafta, the recent breakthrough drug that essentially cures 90% of cystic fibrosis cases.

It doesn't hit the disease at its root, the genetic cause. Instead it uses a combination of three treatments that each addresses one of the mechanisms of the disease.

It seems likely that in mecfs and long covid we have diverse immune system problems that are part of the problem but not the whole problem. A combo treatment that improves several of these measurable problems might create noticeable symptom relief, moving people from severe to moderate. Perhaps it may even generate sfficient relief that the body can then heal the underlying issue, at least for some people.

 

[Jonathan Edwards]

Trendy garbage I am afraid.

 

[Hutan]

Montpellier, France

When the pan- demic was declared in March 2020, it was difficult to believe that the disease could be chronic. Indeed, cases of long COVID were initially dismissed as instances of anxiety, stress, or other mental health issues, and it took some time for the scientific and medical community to recognize the syndrome.2

It wasn't that difficult to believe the disease could be chronic.

With no precise understanding of long COVID's physiopathology, no basic treatment for it has been developed.

But at least this team understands that there is no treatment. (Perhaps 'basic' is a translation error? perhaps meaning 'disease-modifying'?)

I'm aware that Jonathan doesn't think much of the idea of NETs. I can't really evaluate it - it sounds plausible and lots of people have constructed elaborate stories around the concept. The issue that I have so far in the paper is the story of NETs could perhaps fit severe Covid-19, but I think the evidence for it applying to Long Covid isn't really there. e.g.

Low‐density granulocytes (LDGs) are a subset of neutrophils, whose number is associated with COVID‐19 severity. They have been shown to persist with heightened activation phenotype in the circulation long after initial SARS‐CoV‐2 infection.33 In this context, it should be noted that long COVID syndrome has been associated with elevated NETs markers and NET formation on LDGs, as well as with an enhanced proclivity for platelet−neutrophil aggregation (PNA). It is, therefore, credible that the phenotypic alteration of LDGs might account at least in part for post‐ acute sequelae of COVID‐19 (PASC, equivalent to long COVID).

No reference is given for that statement about Long Covid - that it as been associated with elevated NETs markers.

Thus, in concert with fibrin and von Willebrand factor (vWF), NETs contribute to the generation of a pro- thrombotic environment, in particular by constituting the physical scaffold that can generate a venous thrombus.36,42–44

I can't recall what has been found about levels of fibrin and vWF in long Covid - but the authors didn't take the opportunity to point to a paper.

Enzymes anchored on the NETs, such as the NE, MPO, protein3, and cathepsin G, which are responsible for the degradation of micro‐organisms trapped on the NETs, contribute to the permeabilization and activation of endothelial cells, the infiltration of immune cells, and the inflammation of tis- sue.15,19,25 Such tissue damage and endothelial damage has of course been observed in the acute31,35,59,60 and post‐acute phases of COVID‐ 19,1,2 and is linked to the systemic direct cytotoxicity of these enzymes, in particular elastase.46,61,62 These enzymes are initially anchored on the NETs, but are then released into the bloodstream after the NETs' degra- dation, leading to systemic toxicity. Furthermore, it is very likely that the release of mitochondria 63 during the expulsion of chromatin, resulting in particular from the vital process of NETosis,64 leads to a strong activation of the inflammasome.53 The subsequent extracellular degradation of mitochondria results notably in the systemic release of the immunogenic cardiolipin molecules.53,54

The references regarding Long Covid there are
1. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133‐146.
2. Yong SJ. Long COVID or post‐COVID‐19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis. 2021; 53(10):737‐754.
I'd have to have a look at those again, but I didn't think that we had much evidence for inflammation of tissue in long Covid.

Taken as a whole, overproduction of NETs, in addition to the inflammation induced by strong viral infection, over‐ activate or deteriorate the endothelium, thus altering its function, notably its implication in the blood brain barrier.6,57 In this latter context, it should be noted that experimental animal models of chronic neuroinflammation have demonstrated that stimulation of neutrophils increases central nervous system inflammation by degrading blood−brain barrier integrity.6 Such blood−brain barrier disruption has very recently been identified in long COVID‐associated cognitive impairment65 and dysautonomia.66

But, we had Nath saying just the other day that there was no evidence for blood-brain barrier disruption in Long Covid. Of course, he could be wrong but he seemed very sure.

The thing is, severe Covid-19 does involve all sorts of pathology, but people are very sick and it's possible to see inflammation and there are thrombosis-type problems. People are getting Long Covid after even very mild infections. I find it a bit hard to believe that the mechanism is the same.

 

[Jonathan Edwards]

But, we had Nath saying just the other day that there was no evidence for blood-brain barrier disruption in Long Covid. Of course, he could be wrong but he seemed very sure.

One thing I think we can be sure of is that there will be no NETs anywhere near brain endothelium in Long Covid. NETs are clumps of dead neutrophils outside the circulation in the tissue. If that was going on in the brain you would be on ITU with a tube in.

 

[Hutan]

Such blood−brain barrier disruption has very recently been identified in long COVID‐associated cognitive impairment65 and dysautonomia.66

But, we had Nath saying just the other day that there was no evidence for blood-brain barrier disruption in Long Covid. Of course, he could be wrong but he seemed very sure.

I've just looked at reference 65 - thread here
Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment, 2024, Greene et al
Although the cohorts were small (e.g. 11), the results from the MRI with contrast did look pretty good. The paper was from a Trinity College Dublin team and published in Nature Neurology.

So, I'm not sure what to think. Do we know why Nath was so convinced the BBB wasn't involved in Long Covid?