Thread by @ZdenekVrozina

An interesting new review proposes that Long COVID is not just about what keeps the immune system on, but also about what fails to turn it off🧵

This review proposes a striking model for Long COVID. A self sustaining loop in which lingering danger signals keep innate immunity activated, tissue injury generates new inflammatory cues, and the normal transition from inflammation to repair never fully happens.

1. After the acute infection is over, the body may still be exposed to signals that look dangerous to the innate immune system. These could include leftover SARS2 material, reactivated latent viruses, microbial products leaking across damaged mucosal barriers like the gut or nasopharynx, distress signals released by injured tissues themselves.

The immune system may keep seeing reasons to stay activated even after the original illness has passed.

2. Those danger signals are then picked up by pattern recognition receptors. The review highlights TLR2, TLR4, TLR7/8, MDA5, and the cGAS-STING pathway. Once these pathways are triggered, they drive inflammatory signaling, interferon responses, and cytokine production.

3. At the same time, damaged cells release internal alarm molecules like HMGB1, calprotectin, and mitochondrial DNA, which means the body is no longer reacting only to an outside trigger but also to damage coming from its own tissues. That creates a vicious cycle.

4. A major hub in this model is the inflammasome, especially NLRP3. The paper treats NLRP3 as a point where many different stress signals converge. Once activated, it promotes IL-1β and IL-18 release and can drive pyroptosis, an inflammatory form of cell death.

That matters because pyroptosis does not end the story. It spills more danger signals into the tissue, which can reactivate innate immune pathways again. So the loop becomes - trigger, inflammasome activation, cell injury, new danger signals, then more immune activation.

5. But the paper says the problem is not only that the immune system stays on. The second half of the model is that the body’s off-switch is broken. Normally, inflammation does not just fade away by itself.

The body actively resolves it through specialized pro-resolving mediators, by stopping neutrophil recruitment, limiting NET formation, clearing dying cells, shifting macrophages into a repair mode. In this review’s framework, those pro-resolution programs are impaired, so inflammation is not properly shut down and tissue repair does not fully begin.

6. One especially important failure point is efferocytosis, the process where macrophages clear away dying cells. If that cleanup works, the tissue can calm down and move toward repair. If it fails, those dying cells break down further and release even more inflammatory material.

The review suggests that in COVID and PASC, macrophages may fail to do this cleanup properly and may also fail to switch into a repair oriented state. Instead of helping close the wound, they stay stuck in an inflammatory program.

7. The paper then adds a deeper layer - maladaptive trained immunity. This is the idea that the innate immune system can be reprogrammed by infection. According to the review, SARS2 and the inflammatory environment around it may leave long-lasting epigenetic and metabolic marks in myeloid cells and even in hematopoietic stem and progenitor cells in the bone marrow.

So the problem is not only that some immune cells remain activated. It is that the system may keep making new immune cells already biased toward dysfunctional behavior.

8. That helps explain why Long COVID can last so long and look so different from person to person. In some patients, trained innate immunity may become hyperreactive, producing too much inflammatory signaling.

In others, the cells may become exhausted or tolerant, meaning they respond poorly in some ways but remain pathologically dysregulated. The review frames these as possible innate immune endotypes, not necessarily contradictions.

9. This endotype idea is one of the most interesting parts of the paper. Instead of treating Long COVID as one single biological entity, the authors propose that different patients may end up in different immune dominant patterns, such as thromboinflammatory, interferon-driven, or neuroinflammatory forms.

That could explain why studies often report different biomarkers and why symptoms vary so widely. It also suggests that one treatment approach may not fit everyone.

12. So in simple terms.
A lingering source of danger keeps stimulating innate immune sensors.
That drives inflammasomes, cytokines, NETs, complement, and tissue injury. The damaged tissue releases more alarm signals.
At the same time, the body fails to fully activate the systems that should resolve inflammation and promote repair.
Over time, that dysfunctional state becomes reinforced through trained immunity.

13. The big idea of the paper is this.
Long COVID may be less like a simple lingering infection and more like a failed landing after infection. The immune system cannot fully exit emergency mode, and the longer that lasts, the more the state becomes self sustaining.

This is presented as a mechanistic narrative review, not final proof of one universal cause, but it is an interesting attempt to unify many scattered findings into one framework.

Raif at al., Post-acute sequelae of COVID-19: A disorder of impaired innate immune resolution - A narrative review.
sciencedirect.com/science/articl…